Triamide-substituted heterobicyclic compounds

ABSTRACT

The invention relates to triamide MTP/ApoB inhibitors of the formula 1 
                 
 
wherein R 1 -R 8  are as defined in the specification, as well as pharmaceutical compositions and uses thereof, and processes for preparing the compounds. The compounds of the invention are useful for the treatment of obesity and lipid disorders.

This application is a divisional of U.S. patent application Ser. No.10/177,858 filed on Jun. 20, 2002 now U.S. Pat. No. 6,720,351 whichclaims the benefit of U.S. Provisional Patent Application No. 60/301,644filed on Jun. 28, 2001, both of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

This invention relates to triamide-substituted heterobicyclic compounds.These compounds are inhibitors of microsomal triglyceride transferprotein (MTP) and/or apolipoprotein B (Apo B) secretion and are usefulfor the treatment of obesity and related diseases. These compounds arealso useful for the prevention and treatment of atherosclerosis and itsclinical sequelae, for lowering serum lipids, and in the prevention andtreatment of related diseases. The invention further relates topharmaceutical compositions comprising these compounds and to methods oftreating obesity, atherosclerosis, and related diseases and/orconditions with said compounds, either alone or in combination withother medicaments, including lipid lowering agents. Further still, theinvention relates to certain processes and intermediates related theretowhich are useful in the preparation of the compounds of the instantinvention.

BACKGROUND OF THE INVENTION

Microsomal triglyceride transfer protein catalyzes the transport oftriglyceride, cholesteryl ester, and phospholipids and has beenimplicated as a putative mediator in the assembly of Apo B-containinglipoproteins, biomolecules which contribute to the formation ofatherosclerotic lesions. Specifically, the subcellular (lumen of themicrosomal fraction) and tissue distribution (liver and intestine) ofMTP have led to speculation that it plays a role in the assembly ofplasma lipoproteins, as these are the sites of plasma lipoproteinassembly. The ability of MTP to catalyze the transport of triglyceridebetween membranes is consistent with this speculation, and suggests thatMTP may catalyze the transport of triglyceride from its site ofsynthesis in the endoplasmic reticulum membrane to nascent lipoproteinparticles within the lumen of the endoplasmic reticulum.

Accordingly, compounds which inhibit MTP and/or otherwise inhibit Apo Bsecretion are useful in the treatment of atherosclerosis and otherconditions related thereto. Such compounds are also useful in thetreatment of other diseases or conditions in which, by inhibiting MTPand/or Apo B secretion, serum cholesterol and triglyceride levels may bereduced. Such conditions may include, for example, hypercholesterolemia,hypertriglyceridemia, pancreatitis, and obesity; andhypercholesterolemia, hypertriglyceridemia, and hyperlipidemiaassociated with pancreatitis, obesity, and diabetes. For a detaileddiscussion, see for example, Wetterau et al., Science, 258, 999-1001,(1992), Wetterau et al., Biochem. Biophys. Acta., 875, 610-617 (1986),European patent application publication Nos. 0 584 446 A2, and 0 643 057A1, the latter of which refers to certain compounds which have utilityas inhibitors of MTP. Other examples of MTP inhibitors may be found ine.g., U.S. Pat. Nos. 5,712,279, 5,741,804, 5,968,950, 6,066,653, and6,121,283; PCT International Patent Application publications WO96/40640, WO 97/43257, WO 98/27979, WO 99/33800 and WO 00/05201; andEuropean patent application publications EP 584446 and EP 643,057.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula 1:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is substituted at the 5 or 6 position of formula 1 and has thestructure:

m is an integer from 0 to 5;

n is an integer from 0 to 3;

p is an integer from 0 to 3;

L is —C(O)N(R⁹)—, i.e., L has the structure:

X is N or C(R^(c));

R², R⁸, R¹¹, R¹², R¹³ and R¹⁶ are each independently selected from halo,cyano, nitro, azido, amino, hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkoxy,methoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,perfluoro(C₂-C₄)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino-, (C₁-C₆)dialkylamino, amino(C₁-C₆)alkyl-,—(CR^(a)R^(b))_(q)NR^(a)R¹⁴, —C(O)NR^(a)R¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴OR¹⁵,—CH═NOR¹⁵, —NR¹⁴C(O)OR¹⁵, —NR¹⁴S(O)_(j)R¹⁵, —C(O)R¹⁵, —C(S)R¹⁵,—C(O)OR¹⁵, —OC(O)R¹⁵, —SO₂NR^(a)R¹⁴, —S(O)_(j)R¹⁵, or—(CR^(a)R^(b))_(q)S(O)_(j)R¹⁵;

each R^(a) and R^(b) is independently H or (C₁-C₆)alkyl;

R^(c) is H or R¹¹;

each q is independently an integer from 0 to 6;

each j is independently 0, 1 or 2;

R³ is H, halo, (C₁-C₆)alkyl, or mono-, di- or tri-halo(C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵, —SO₂R¹⁵ or—(CR^(a)R^(b))_(q)-phenyl, wherein the phenyl moiety is optionallysubstituted with from one to five independently selected R¹⁶;

each r is independently an integer from 2 to 5;

each t is independently an integer from 1 to 6;

R⁵, R⁶ and R⁹ are each independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,—C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵;

R⁷ is phenyl, pyridyl, phenyl-Z¹- or pyridyl-Z¹-, wherein the phenyl orpyridyl moiety is optionally substituted with one to five independentlyselected R¹²;

Z¹ is —SO₂— or —(CR^(a)R^(b))_(v)—;

v is independently an integer from 1 to 6;

R¹⁰ is phenyl, pyridyl, phenyl-Z²- or pyridyl-Z²-, wherein the phenyl orpyridyl moiety is optionally substituted with one to five independentlyselected R¹³;

Z² is —S(O)_(j)—, —O—, —(CR^(a)R^(b))_(w)—, or—(O)_(k)(CR^(a)R^(b))_(w)(O)_(k)(CR^(a)R^(b))_(q)—;

w is independently an integer from 1 to 6;

each k is independently 0 or 1;

each R¹⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵,—C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(t)R¹⁵ or —SO₂R¹⁵;

each R¹⁵ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, wherein the alkyl,moieties of the foregoing R¹⁵ groups are independently optionallysubstituted with 1 to 3 substituents independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyland trifluoromethoxy;

and wherein any of the above “alkyl”, “alkenyl” or “alkynyl” moietiescomprising a CH₃ (methyl), CH₂ (methylene), or CH (methine) group whichis not substituted with halogen, SO or SO₂, or attached to a N, O or Satom, optionally bears on said methyl, methylene or methine group asubstituent selected from the group consisting of halo, —OR^(a), —SR^(a)and —NR^(a)R^(b).

In an embodiment of the invention, L is attached to the 2 position of R¹and to the 5 position of formula 1, i.e., the compound of formula 1 hasthe structure of formula 1a:

In another embodiment of the invention, L is attached to the 2 positionof R¹ and to the 5 position of formula 1, and R¹⁰ is attached at the 3′position.

In another embodiment of the invention, L is attached to the 3 positionof R¹ and to the position formula 1. In another embodiment of theinvention, L is attached to the 3 position of R¹ and to the 5 positionof formula 1 and X is N. In still another embodiment of the invention, Lis attached to the 3 position of R¹ and to the 5 position of formula 1,X is N and R¹⁰ is attached at the 2 position of R¹. In other embodimentsof the invention, the attachment of L to R¹ is selected from the 3, 4, 6or 6 position and the attachment of L to the compound of formula 1 isselected from the 5 position or 6 position.

In another embodiment of the invention, X is C(R^(c)).

In another embodiment of the invention, X is C(R^(c)), m is 0, n is 0,and p is 0 or 1.

In another embodiment of the invention, X is C(R^(c)), m is 0, n is 0,and p is 0 or 1, and R¹⁰ is phenyl-Z²- attached at the 3 position of R¹,wherein the phenyl moiety of R¹⁰ is optionally substituted with one tofive independently selected R¹³.

In another embodiment of the invention, X is C(R^(c)), m is 0, n is 0,and p is 0 or 1, and R¹⁰ is phenyl attached at the 3 position of R¹,wherein the phenyl moiety of R¹⁰ is optionally substituted with one tofive independently selected R¹³.

In another embodiment of the invention, R⁷ is phenyl-Z¹, wherein thephenyl moiety is optionally substituted with one to five independentlyselected R¹². In a preferred embodiment of the invention, Z¹ is—(CR^(a)R^(b))_(v)—, and in a more preferred embodiment, Z¹ ismethylene, i.e., —CH₂—.

In another embodiment of the invention, R⁴, R⁵, R⁶ and R⁹ are eachindependently selected from H, (C₁-C₆)alkyl, —(CR^(a)R^(b))_(q)O(C₁-C₆alkyl) or —(CR^(a)R^(b))_(r)R¹⁵.

In another embodiment of the invention, each R¹² is independentlyselected from halo, hydroxy, (C₁-C₆)alkyl, methoxy, (C₂-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, mono-, di- ortri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy, (C₁-C₆)alkylthioand hydroxy(C₁-C₆)alkyl.

In another embodiment of the invention, each R¹³ is independentlyselected from halo, hydroxy, amino, cyano, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,methoxy, (C₂-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- ortri-halo(C₂-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl, —C(O)OR¹⁵ and —NR¹⁴C(O)R¹⁵;wherein R¹⁴ is H or (C₁-C₆)alkyl; and wherein R¹⁵ is H or (C₁-C₆)alkyl.

In another embodiment of the invention, R¹⁰ is phenyl attached at the 3position of R¹, wherein the phenyl moiety of R¹⁰ is optionallysubstituted with one R¹³. In a preferred embodiment, R¹⁰ and R¹ both arephenyl, such that R¹ and R¹⁰ together form a 1,1′-biphenyl group,wherein R¹⁰ comprises the 1′-6′ positions of the biphenyl group and R¹³is substituted at the 4′ position of the biphenyl.

In another embodiment of the invention, R⁴ is H, (C₁-C₆)alkyl or—(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl).

In another embodiment of the invention, the carbon designated “a” informula 1 is in the “(S)” configuration.

In a preferred embodiment of the invention, R¹³ is trifluoromethyl.

In another preferred embodiment of the invention, R³ is H, halo, or(C₁-C₆)alkyl.

In a more preferred embodiment of the invention, R⁶ is methyl.

In a particularly preferred embodiment of the invention, the compound offormula 1 is(S)-1-ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide.

In another particularly preferred embodiment of the invention, thecompound of formula 1 is(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide.

In another more preferred embodiment of the invention R³ is chloro.

In another particularly preferred embodiment of the invention, thecompound of formula 1 is selected from the group consisting of:

3-chloro-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide;

3-chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide;

4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-({[(benzyl-methyl-carbamoyl)-phenyl-methyl]-methyl-amino}-methyl)-3-chloro-1-methyl-1H-indol-5-yl]-amide,which is alternately named:3-chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid {N-[2-(benzyl(methyl)amino)-2-oxo-1-phenylethyl]methyl}amide;

3-chloro-1-methyl-5-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide; and

3-chloro-1-ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide.

In another embodiment of the invention, X is C(R^(c)), m is 0, n is 0,and p is 0 or 1, and R¹⁰ is phenyl-Z²- attached at the 3′-position,wherein the phenyl moiety of R¹⁰ is optionally substituted with one tofive independently selected R¹³ and Z² is O or S.

In another embodiment of the invention, R⁷ is phenyl-Z¹, wherein thephenyl moiety is optionally substituted with one to five independentlyselected R¹² and Z¹ is O or S.

In another embodiment of the invention, R⁷ is pyridyl-Z¹, wherein thepyridyl moiety is optionally substituted with from one to fiveindependently selected R¹². In a preferred embodiment thereof, Z¹ is—(CH₂)—.

In another embodiment of the invention, X is N and R¹⁰ is phenyloptionally substituted with one to five independently selected R¹³.

In another embodiment of the invention, X is N and R¹⁰ is phenyloptionally substituted with one to five independently selected R¹³, andR⁷ is phenyl-Z¹, wherein the phenyl moiety is optionally substitutedwith from one to five independently selected R¹².

The present invention also relates to a compound of the formula 1b:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is substituted at the 5 or 6 position of formula 1b and has thestructure:

or when R⁷ is phenyl, pyridyl, phenyl-Z¹-or pyridyl-Z¹- optionallysubstituted with one to five independently selected R¹², R¹ is(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₁₀)bicycloalkyl,—(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵, —SO₂R¹⁵,(C₄-C₁₀)heterocyclyl, (C₅-C₁₀)heteroaryl, aryl or—(CR^(a)R^(b))_(q)-aryl, wherein the cycloalkyl, heterocyclyl,heteroaryl or aryl moiety is optionally substituted with from one tofive independently selected R¹⁶;

m is an integer from 0 to 5;

n is an integer from 0 to 3;

p is an integer from 0 to 3;

L is —C(O)N(R⁹)—, as described above;

X¹ is N(R⁴), S or O;

X² is N or C(R^(c));

R², R⁸, R¹¹, R¹², R¹³ and R¹⁶ are each independently selected from halo,cyano, nitro, azido, amino, hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkoxy,methoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,perfluoro(C₂-C₄)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino-, (C₁-C₆)dialkylamino, amino(C₁-C₆)alkyl-,—(CR^(a)R^(b))_(q)NR^(a)R¹⁴, —C(O)NR^(a)R¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴OR¹⁵,—CH═NOR¹⁵, —NR¹⁴C(O)OR¹⁵, —NR¹⁴S(O)_(j)R¹⁵, —C(O)R¹⁵, —C(S)R¹⁵,—C(O)OR¹⁵, —OC(O)R¹⁵, —SO₂NR^(a)R¹⁴, —S(O)_(j)R¹⁵, or—(CR^(a)R^(b))_(q)S(O)_(j)R¹⁵;

each R^(a) and R^(b) is independently H or (C₁-C₆)alkyl;

R^(c) is H or R¹¹;

each q is independently an integer from 0 to 6;

each j is independently 0, 1 or 2;

R³ is H, halo, (C₁-C₆)alkyl, or mono-, di- or tri-halo(C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵, —SO₂R¹⁵ or—(CR^(a)R^(b))_(q)-phenyl, wherein the phenyl moiety is optionallysubstituted with from one to five independently selected R¹⁶;

each r is independently an integer from 2 to 5;

each t is independently an integer from 1 to 6;

R⁵ and R⁹ are each independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,—C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵;

-   -   R⁶ is H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,        —(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(q)S(C₁-C₆        alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵ or        —SO₂R¹⁵;

y is an integer from 0 to 5;

R⁷ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,—(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(q)S(C₁-C₆ alkyl);(C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)C(S)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵;

or R⁷ is phenyl, pyridyl, phenyl-Z¹-or pyridyl-Z¹- optionallysubstituted with one to five independently selected R¹²;

or R⁶ and R⁷ taken together with the nitrogen atom to which they areattached together comprise (C₄-C₁₀)heterocyclyl, wherein theheterocyclyl moiety is monocyclic;

wherein the alkyl, cycloalkyl, and heterocyclyl moieties of theforegoing R⁶ and R⁷ groups are optionally substituted independently with1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—OC(O)R¹⁵, —NR¹⁴C(O)R¹⁵, —C(O)NR^(a)R¹⁴, —NR^(a)R¹⁴, and —NR¹⁴OR¹⁵,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; and

R¹⁰ is phenyl, pyridyl, phenyl-Z²- or pyridyl-Z²-, wherein the phenyl orpyridyl moiety is optionally substituted with one to five independentlyselected R¹³;

Z² is —S(O)_(j)—, —O—, —(CR^(a)R^(b))_(w)—, or—(O)_(k)(CR^(a)R^(b))_(w)(O)_(k)(CR^(a)R^(b))_(q)—;

w is independently an integer from 1 to 6;

each k is independently 0 or 1;

or R¹⁰ is OR¹⁷, wherein R¹⁷ is (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,mono-, di- or tri-halo(C₂-C₆)alkyl, perfluoro(C₂-C₄)alkyl,trifluoromethyl(C₁-C₅)alkyl, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl;

each R¹⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵,—C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(t)R¹⁵ or —SO₂R¹⁵;

each R¹⁵ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, wherein the alkyl,moieties of the foregoing R¹⁵ groups are independently optionallysubstituted with 1 to 3 substituents independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyland trifluoromethoxy;

and wherein any of the above “alkyl”, “alkenyl” or “alkynyl” moietiescomprising a CH₃ (methyl), CH₂ (methylene), or CH (methine) group whichis not substituted with halogen, SO or SO₂, or attached to a N, O or Satom, optionally bears on said methyl, methylene or methine group asubstituent selected from the group consisting of halo, —OR^(a), —SR^(a)and —NR^(a)R^(b).

In an embodiment of the invention, X² is C(R^(c)).

In another embodiment of the invention, X² is C(R^(c)) and L is attachedto the 2 position of R¹ and to the 5 position of formula 1b.

In another embodiment of the invention, X² is C(R^(c)) and L is attachedto the 2 position of R¹ and to the 5 position of formula 1b, R¹⁰ is OR¹⁷and R⁷ is phenyl-Z¹, wherein the phenyl moiety is optionally substitutedwith one to five independently selected R¹². In a preferred embodimentthereof, Z¹ is —(CR^(a)R^(b))_(t)—.

In another embodiment of the invention, X² is C(R^(c)) and L is attachedto the 2 position of R¹ and to the 5 position of formula 1b, and R¹⁰ isphenyl attached at the 3 position of R¹, wherein the phenyl moiety ofR¹⁰ is optionally substituted with one to five independently selectedR¹³. In a preferred embodiment of the invention, R⁶ in formula 1b is Hor (C₁-C₄)alkyl.

In another preferred embodiment of the invention, the carbon designated“a” in formula 1b is in the (S) absolute configuration.

In another embodiment of the invention, R¹³ in formula 1b is H ortrifluoromethyl.

In another preferred embodiment of the invention, R³ in formula 1b is H,halo, or (C₁-C₆)alkyl

In another preferred embodiment of the invention, R⁷ in formula 1b is(C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl.

In a particularly preferred embodiment of the invention, the compound isselected from the group consisting of:

3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-oxo-1-phenyl-2-(prop-2-ynylamino)ethyl]amide;

3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-(isopropylamino-2-oxo-1-phenylethyl)amide;

3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-oxo-1-phenyl-2-(propylamino)ethyl]amide;

3-Chloro-1-methyl-5-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-(ethylamino)-2-oxo-1-phenylethyl]amide;

3-Chloro-1-methyl-5-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-(isopropylamino-2-oxo-1-phenylethyl]amide;

5-[(Biphenyl-2-carbonyl)-amino]-3-chloro-1-methyl-1H-indole-2-carboxylicacid [2-oxo-1-phenyl-2-(propylamino)ethyl]amide; and

5-[(Biphenyl-2-carbonyl)-amino]-3-chloro-1-methyl-1H-indole-2-carboxylicacid [2-(isopropylamino-2-oxo-1-phenylethyl]amide.

In an embodiment of the invention, R⁶ and R⁷ in formula 1b takentogether with the nitrogen atom to which they are attached togethercomprise (C₄-C₁₀)heterocyclyl, wherein the heterocyclyl is optionallysubstituted independently with 1 or 2 substituents independentlyselected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl andtrifluoromethyl. In a preferred embodiment thereof, the heterocyclyl isselected from pyrrolidinyl, piperidinyl, morpholino and thiomorpholino.In a particularly preferred embodiment thereof, the heterocyclyl ispyrrolidinyl or morpholino.

The present invention also relates to compounds of the formula 2:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is substituted at the 5 or 6 position of formula 1 and has thestructure:

m is an integer from 0 to 5;

n is an integer from 0 to 3;

p is an integer from 0 to 3;

L is —C(O)N(R⁹)—;

X is N or C(R^(c));

R², R⁸, R¹¹, R¹² and R¹³ are each independently selected from halo,cyano, nitro, azido, amino, hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkoxy,methoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,perfluoro(C₂-C₄)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino-, (C₁-C₆)dialkylamino, amino(C₁-C₆)alkyl-,—(CR^(a)R^(b))_(q)NR^(a)R¹⁴, —C(O)NR^(a)R¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴OR¹⁵,—CH═NOR¹⁵, —NR¹⁴C(O)OR¹⁵, —NR¹⁴S(O)_(j)R¹⁵, —C(O)R¹⁵, —C(S)R¹⁵,—C(O)RO¹⁵, —OC(O)R¹⁵, —SO₂NR^(a)R¹⁴, —S(O)_(j)R¹⁵, or—CR^(a)R^(b))_(q)S(O)_(j)R¹⁵;

each R^(a) and R^(b) is independently H or (C₁-C₆)alkyl;

R^(c) is H or R¹¹;

each q is independently an integer from 0 to 6;

each j is independently 0, 1 or 2;

R³ is H, halo, (C₁-C₆)alkyl, or mono-, di- or tri-halo(C₁-C₆)alkyl;

each r is independently an integer from 2 to 5;

each t is independently an integer from 1 to 6;

R⁵ and R⁹ are each independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,—C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵;

R⁶ is H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(q)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵;

y is an integer from 0 to 5;

R⁷ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,—(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(q)S(C₁-C₆ alkyl);(C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)C(S)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵;

or R⁷ is phenyl, pyridyl, phenyl-Z¹-or pyridyl-Z¹- optionallysubstituted with one to five independently selected R¹²;

or R⁶ and R⁷ taken together with the nitrogen atom to which they areattached together comprise (C₄-C₁₀)heterocyclyl, wherein theheterocyclyl moiety is monocyclic;

wherein the alkyl, cycloalkyl, and heterocyclyl moieties of theforegoing R⁶ and R⁷ groups are optionally substituted independently with1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—OC(O)R¹⁵, —NR¹⁴C(O)R¹⁵, —C(O)NR^(a)R¹⁴, —NR^(a)R¹⁴, and —NR¹⁴OR¹⁵,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl; and

R¹⁰ is phenyl, pyridyl, phenyl-Z²- or pyridyl-Z²-, wherein the phenyl orpyridyl moiety is optionally substituted with one to five independentlyselected R¹³;

Z² is —S(O)_(j)—, —O—, —(CR^(a)R^(b))_(w)—, or—(O)_(k)(CR^(a)R^(b))_(w)(O)_(k)(CR^(a)R^(b))_(q)—;

w is independently an integer from 1 to 6;

each k is independently 0 or 1;

or R¹⁰ is OR¹⁷, wherein R¹⁷ is (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,mono-, di- or tri-halo(C₂-C₆)alkyl, perfluoro(C₂-C₄)alkyl,trifluoromethyl(C₁-C₅)alkyl, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl;

each R¹⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵,—C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(t)R¹⁵ or —SO₂R¹⁵;

each R¹⁵ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, wherein the alkyl,moieties of the foregoing R¹⁵ groups are independently optionallysubstituted with 1 to 3 substituents independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyland trifluoromethoxy;

and wherein any of the above “alkyl”, “alkenyl” or “alkynyl” moietiescomprising a CH₃ (methyl), CH₂ (methylene), or CH (methine) group whichis not substituted with halogen, SO or SO₂, or attached to a N, O or Satom, optionally bears on said methyl, methylene or methine group asubstituent selected from the group consisting of halo, —OR^(a), —SR^(a)and —NR^(a)R^(b).

In an embodiment of the invention, X in formula 2 is C(R^(c)).

In another embodiment of the invention, L in formula 2 is attached tothe 2 position of R¹ and to the 5 position of formula 2.

In another embodiment of the invention, wherein y is 1 or 2.

In another embodiment of the invention, R¹⁰ in formula 2 is phenylattached at the 3 position of R¹, wherein the phenyl moiety of R¹⁰ isoptionally substituted with one to five independently selected R¹³.

In another embodiment of the invention, R⁷ in formula 2 is phenyl-Z¹,wherein the phenyl moiety is optionally substituted with one to fiveindependently selected R¹². In a preferred embodiment thereof, Z¹ is—(CR^(a)R^(b))_(t)—.

In another embodiment of the invention, R⁶ in formula 2 is H or(C₁-C₄)alkyl.

In another embodiment of the invention, the carbon designated “a” informula 2 is in the (S) absolute configuration.

In a preferred embodiment of the invention, R¹³ in formula 2 istrifluoromethyl.

In another preferred embodiment of the invention, R³ in formula 2 is H,halo, or (C₁-C₆)alkyl.

The invention also relates to a process for preparing a compound offormula 1 which comprises forming an amide linkage between a compound ofthe formula AB1:

and a compound of the formula C:

wherein

m is an integer from 0 to 5; n is an integer from 0 to 3; p is aninteger from 0 to 3;

the amido nitrogen atom of —C(O)N(R⁹)— above is bonded to the 5 or 6position of the indole;

X is N or C(R^(c)), wherein R^(c) is H or R¹¹;

R², R⁸, R¹¹, R¹², R¹³ and R¹⁶ are each independently selected from halo,cyano, nitro, azido, amino, hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkoxy,methoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,perfluoro(C₂-C₄)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino-, (C₁-C₆)dialkylamino, amino(C₁-C₆)alkyl-,—(CR^(a)R^(b))_(q)NR^(a)R¹⁴, —C(O)NR^(a)R¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴OR¹⁵,—CH═NOR¹⁵, —NR¹⁴C(O)OR¹⁵, —NR¹⁴S(O)_(j)R¹⁵, —C(O)R¹⁵, —C(S)R¹⁵,—C(O)OR¹⁵, —OC(O)R¹⁵, —SO₂NR^(a)R¹⁴, —S(O)_(j)R¹⁵, or—(CR^(a)R^(b))_(q)S(O)_(j)R¹⁵;

each R^(a) and R^(b) is independently H or (C₁-C₆)alkyl;

each q is independently an integer from 0 to 6; each j is independently0, 1 or 2;

R³ is H, halo, (C₁-C₆)alkyl, or mono-, di- or tri-halo(C₁-C₆)alkyl;

R⁴ is H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵, —SO₂R¹⁵ or—(CR^(a)R^(b))_(q)-phenyl, wherein the phenyl moiety is optionallysubstituted with from one to five independently selected R¹⁶;

each r is independently an integer from 2 to 5; each t is independentlyan integer from 1 to 6;

R⁵, R⁶ and R⁹ are each independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,—C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵;

R⁷ is phenyl, pyridyl, phenyl-Z¹- or pyridyl-Z¹-, wherein the phenyl orpyridyl moiety is optionally substituted with one to five independentlyselected R¹²;

Z¹ is —SO₂— or —(CR^(a)R^(b))_(v)—;

v is independently an integer from 1 to 6;

R¹⁰ is phenyl, pyridyl, phenyl-Z²- or pyridyl-Z²-, wherein the phenyl orpyridyl moiety is optionally substituted with one to five independentlyselected R¹³;

Z² is —S(O)_(j)—, —O—, —(CR^(a)R^(b))_(w)—, or—(O)_(k)(CR^(a)R^(b))_(w)(O)_(k)(CR^(a)R^(b))_(q)—;

w is independently an integer from 1 to 6;

each k is independently 0 or 1;

each R¹⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵,—C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(t)R¹⁵ or —SO₂R¹⁵;

each R¹⁵ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, wherein the alkyl,moieties of the foregoing R¹⁵ groups are independently optionallysubstituted with 1 to 3 substituents independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyland trifluoromethoxy;

and wherein any of the above “alkyl”, “alkenyl” or “alkynyl” moietiescomprising a CH₃ (methyl), CH₂ (methylene), or CH (methine) group whichis not substituted with halogen, SO or SO₂, or attached to a N, O or Satom, optionally bears on said methyl, methylene or methine group asubstituent selected from the group consisting of halo, —OR^(a), —SR^(a)and —NR^(a)R^(b);

and L^(c) is selected from a (i) a carboxylic acid or salt thereof (ii)an activated form of the carboxylic acid or (iii) an aldehyde.

In an embodiment, the carboxylic acid is optionally activated in-situ,using methods well known in the art. The above process is referred toherein as “Process I.” Process I is applicable to, and provides, aprocess for preparing each of the embodiments, preferred embodiments,more preferred embodiments and particularly preferred embodiments of thecompound of formula 1, a detailed repetition of which is avoided forbrevity. Methods for forming amide linkages are well-known in the art,some examples of which are provided herein.

In an embodiment, the employed form of the amine C may optionally be asalt with any acid that is compatible with the subsequent processoptions, and may additionally or optionally be a solution in a similarlycompatible solvent or mixture of solvents.

In an embodiment, the employed forms of the carboxylic acid (or saltthereof) AB1 and amine C (or salt thereof) optionally include solvatesand hydrates.

In an embodiment of Process I, the amide linkage between AB1 and C isformed by combining AB1, C, and PyBroP (about 1 eq) in a suitablenon-aqueous solvent, followed by the addition of diisopropylethylamine(2-3 eq). In a preferred embodiment, the suitable solvent is methylenechloride or DMF. In a more preferred embodiment of Process I, thesolvent is methylene chloride. In another preferred embodiment, ProcessI further comprises stirring or agitating the resulting mixture at roomtemperature for a period of from about 30 minutes to about 24 hours. Inanother preferred embodiment thereof, of Process I further comprisesremoval of the solvent and the purification of the product by TLC orflash chromatography using ethyl acetate/hexane as the eluting solvent.

In another embodiment of Process I, the amide linkage between AB1,wherein LC is an aldehyde, preferably C(O)H, and C is formed by aprocess (herein, the “Aldehyde Process”) which comprises (a) reactingthe AB1 aldehyde with C in the presence of an acid, preferably aceticacid, in a suitable solvent, preferably methylene chloride, followed by(b) addition of NaB(OAc)₃H and chloroform. In an preferred embodiment ofthe Aldehyde Process, the compound of formula 1 is purified from theorganic layer, preferably by flash chromatography usingmethanol/chloroform. In a further embodiment of the Aldehyde Process,the AB1 aldehyde is formed by (i) combining a compound of formula AB1,wherein L^(c) is a carboxylic acid, preferably —COOH, with N,O-dimethylhydroxylamine hydrochloride salt and PyBroP in a suitable solvent;followed by (ii) addition of diisopropylethylamine and (iii) treatmentof the resulting N,O-dimethyl hydroxyamide with DIBAL in a suitablesolvent, to yield the corresponding aldehyde. In a preferred embodimentof the Aldehyde Process, the suitable solvent in step (i) is methylenechloride. In another preferred embodiment of the Aldehyde Process, thesuitable solvent in step (iii) is THF.

In a preferred embodiment of Process I, referred to herein as “ProcessIC” for its use of carbodiimide, the amide linkage between AB1 and C,wherein L^(c) is a carboxylic acid, is formed by (a) combining AB1 witha carbodiimide and a catalyst, e.g., 1-hydroxybenzotriazole hydrate(“HOBt”), in a suitable non-aqueous solvent, and (b) addingtriethylamine and C to the mixture of step (a). In a more preferredembodiment of Process IC, the carbodiimide is EDC, i.e.,1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride, and evenmore preferably, the solvent is methylene chloride. In anotherembodiment, Process IC further comprises at least a second addition oftriethylamine. In another embodiment, Process IC further comprises atleast a second addition of triethylamine, optionally with furtheraddition of the carbodiimide. In another embodiment of Process IC, asalt of the acid AB1 is used in step (a). Preferably, the salt is asodium salt, i.e., L^(c) is —C(O)O⁻Na⁺, and more preferably, the salt isa potassium salt, i.e., L^(c) is —C(O)O⁻K⁺ and particularly preferably,the salt is a potassium salt, i.e., L^(c) is —C(O)O⁻K⁺, crystallizing asthe 2.5 mole hydrate. In a still further embodiment thereof, the acidsalt AB1 is first treated with aqueous acid before combination with theother components in step (a); in this embodiment, the treatment withaqueous acid resulting in precipitation of the free acid as a solid,which is collected for use in step (a). In a preferred embodiment of theacid treatment step, the acid salt AB1 is treated with aqueous acidadjusted to a pH of from about 3 to about 4, with heating. In a morepreferred embodiment, the acid salt is treated with an inert mineralacid, most preferably concentrated aqueous hydrochloric acid, oralternatively, an inert organic acid, preferably anhydrous and mostpreferably methanesulfonic acid, before step (a). In a still furtherembodiment, the compound of formula 1 is purified by (a) washing insaturated aqueous sodium hydrogen carbonate, (b) washing in aqueousacid, preferably, hydrochloric acid, and (c) washing with water, toprovide purified compound of formula 1 in the non-aqueous solvent. In astill further embodiment, the non-aqueous solvent is replaced with amylacetate, amyl alcohol, mixtures of methanol or acetonitrile withdiisopropyl ether, or preferably mixtures of propan-2-ol and tert-butylmethyl ether, by distillation, and the solution is cooled in order toprecipitate solid forms, e.g., polymorphs, of the compound of formula 1.Preferably, the solution of compound of formula 1 in mixtures ofpropan-2-ol and tert-butyl methyl ether is seeded with the desired solidform to facilitate precipitation of the desired solid form.

In another embodiment of the above process, the amide linkage betweenAB1 and C is formed by (a) reaction of the acid the1,1′-carbonyldiiimidazole to produce its acyl imidazolide, i.e.,yielding e.g., L^(c)=—C(O)(1-C₃H₃N₂), and (b) reacting the imidazolideof AB1 with C, preferably in the presence of a suitable base. In thisembodiment, some racemization of chiral center “a” in (S)-phenylglycinederivatives has been observed, thus, where preservation ofstereochemistry is desirable, the use of the imidazolide reaction isless preferred than other embodiments described above. Preferredprocesses of the invention preserve the stereochemistry of thephenylglycine group.

In a preferred embodiment of each of the embodiments of Process I andProcess IC, R⁵ is hydrogen, R⁶ is hydrogen, R⁷ is benzyl, m, n and p areall 0, and the carbon designated “a” in formula C is in the (S)configuration. In another preferred embodiment of Process I, the amidelinkage between AB1 and C is formed as in Example 45, step (g).

In a preferred embodiment of Process IC, R⁴ is methyl, R⁵ is hydrogen,R⁶ is methyl, R⁷ is benzyl, m is 0 and the carbon designated “a” informula C is in the (S) configuration and the amide linkage between AB1and C is formed as in Example 44, step (f).

Additional embodiments of methods for forming the amide linkages of theprocesses of this invention are described in the Examples, and it is tobe understood that each of the embodiments exemplified as describedbelow are intended to be included within the scope of the processes ofthis invention.

In a further embodiment of the above process, the compound of formulaAB1 is prepared by a process which comprises forming an amide linkagebetween a compound of the formula A:

and a compound of the formula B1:

wherein L^(c) is a carboxylic acid and L^(e) is a carboxylic acid(C₁-C₆)alkyl ester, and R²-R¹¹ are as defined above.

In an embodiment, the amide linkage between A and B1 is formed by aprocess comprising (a) combining A and B1 with a suitable base, e.g.DIEA, a carbodiimide, e.g., EDC.HCl, and a catalyst, e.g. HOBT, in anorganic solvent, e.g. DMF, followed by (b) distillation of volatilecomponents, (c) partition between organic solvent and dilute aqueousacid, (d) replacement by distillation of the solvent with a non-solvent,e.g. tert-butyl methyl ether, diisopropyl ether or propan-1-ol, and (e)isolation of the product AB1-e by filtration.

In another embodiment, the amide linkage between A and B1 is formed by aprocess comprising (a) combining A with a chlorinating agent, e.g.oxalyl chloride or preferably thionyl chloride, in a compatible solvente.g. toluene, acetonitrile, or 1,2-dichloroethane, in the presence of acatalyst to prepare the acid chloride, i.e. A wherein L^(c)=—C(O)Cl, (b)optionally removing the excess reagent by distillation, (c) combiningthe acid chloride with B1 in the presence of a suitable base, e.g. DIEA,in compatible solvents, e.g. DCE, Toluene, EtOAc, acetonitrile, andmixtures thereof, followed by (d) isolation of product AB1-e asdescribed in the preceding embodiment, or preferably by filtration ofcrude product from the reaction mixture, and reslurry of the crude insuitable non-solvents, preferably in mixtures of aqueous propan-2-ol,before refiltration.

A preferred feature of the above embodiment is the use of catalysis inthe preparation of the acid chloride, i.e. A wherein L^(c)=—C(O)Cl, toprevent the formation of the corresponding symmetrical carboxylicanhydride. Preferred catalysts are tertiary amides, e.g. DMF and DMAC,or pyridines, e.g. pyridine or DMAP or mixtures thereof. More preferredcatalysts are tertiarybenzamides, e.g. N,N-dimethylbenzamide. Even morepreferred catalysts are N-alkyl lactams, e.g. N-methylpyrrolidinone.Catalysis by iron salts and by tetraalkylureas, e.g. tetramethylurea, isknown in the art.

The invention also relates to a compound of the formula AB1:

wherein R³ is H, halo or (C₁-C₆)alkyl, R⁴ and R⁹ are each independentlyH or (C₁-C₆)alkyl; m, n, and p are all 0, R¹⁰ is phenyl optionallysubstituted with from one to five R¹³ groups and L^(c) is a carboxylicacid or salt thereof. In a preferred embodiment, L^(c) is COOH. Inanother preferred embodiment, L^(c) is a salt of the carboxylic acid,preferrably L^(c) is the sodium salt of the carboxylic acid, i.e.,—COO⁻Na⁺, more preferably L^(c) is the potassium salt of the carboxylicacid, i.e., —COO⁻K⁺, and particularly preferably L^(c) is the potassiumsalt of the carboxylic acid, i.e., —COO⁻K⁺, crystallizing as a 2.5 molehydrate. In a preferred embodiment of the compound of formula AB1, R³ isH or halo, R⁴ is methyl, ethyl or propyl; m, n and p are both 0, and R¹⁰is phenyl optionally substituted with one or two R¹³ groups. In a morepreferred embodiment thereof, R³ is H and R⁴ is methyl. In another morepreferred embodiment thereof, R³ is H, R⁴ is methyl and R¹⁰ is phenyloptionally substituted with one R¹³ group. In a particularly preferredembodiment, R³ is H, R⁴ is methyl and R¹⁰ is phenyl substituted with onetrifluoromethyl group. In a particularly preferred embodiment thereof,the trifluoromethyl group is in the 4′ position of the biphenyl groupformed between R¹⁰ and the phenyl to which it is attached.

The invention also relates to a compound of the formula AB1-e, whereinR²-R¹¹ are as defined above for the compound AB1, and L^(e) is acarboxylic acid ester. In an embodiment, the ester is an alkyl ester,preferably a (C₁-C₆) alkyl ester or a substituted-alkyl variationthereon. In a preferred embodiment, L^(e) is the ethyl carboxylic acidester, i.e., —C(O)OCH₂CH₃. In another preferred embodiment, L^(e) is themethyl carboxylic acid ester, i.e., —C(O)OCH₃.

The invention also relates to process for preparing a compound offormula C:

or a stereoisomer thereof, which comprises reacting an amine of theformula HNR⁶R⁷ with a compound of the formula:

wherein R^(p) is H or a protecting group.

In an embodiment, the protecting group is tert-butyloxycarbonyl (“BOC”).In another embodiment, the process comprises combining C′ with acatalyst, e.g. HOBt, and a carbodiimide in a suitable solvent, andadding the amine HNR⁶R⁷. In a preferred embodiment, the carbodiimide isN,N′-dicyclohexylcarbodiimide. In another preferred embodiment, thecarbodiimide is EDC. In another preferred embodiment, the suitablesolvent is dichloromethane. In a preferred embodiment, the mixture ofC′, the amine HNR⁶R⁷, HOBt and carbodiimide is stirred for about 30minutes to 24 hours before further processing. In an embodiment, thefurther processing comprises an aqueous work-up to provide the compoundof formula C. In a preferred embodiment, the amine HNR⁶R⁷ isN-methylbenzylamine, i.e., R⁶ is methyl and R⁷ is benzyl. In anotherpreferred embodiment, R^(p) is BOC and the amine is N-methylbenzylamine,and in a more preferred embodiment thereof, the resulting compound offormula C, (tert-butyl(RS)-2-(benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate), is treatedwith trifluorocaetic acid and triethylsilane in dichloromethane,followed by aqueous workup to yield(RS)-N-benzyl-N-methyl-2-phenylglycinamide. In a particularly preferredembodiment, R^(p) is BOC and the amine is N-methylbenzylamine, and in amore preferred embodiment thereof, the resulting optically enrichedcompound of formula C, (tert-butyl(S)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate), is treatedwith concentrated hydrochloric acid in propan-2-ol, followed byadvantageous precipitation of (S)-N-benzyl-N-methyl-2-phenylglycinamidehydrochloride monohydrate from mixtures of propan-2-ol and tert-butylmethyl ether, resulting in a useful increase in the degree of opticalenrichment.

A salt of the phenylglycine amide may be prepared, e.g., by treating theamide, e.g., (RS)-N-benzyl-N-methyl-2-phenylglycinamide, withdi(o-toluoyl)-L-tartaric acid in a suitable solvent, e.g. ethyl acetate,to provide the di(o-toluoyl)-L-tartrate) salt, e.g.(RS)-N-benzyl-N-methyl-2-phenylglycinamide. Tartrate salts of thephenylglycine amides may be broken to provide the amide, which may bepurified as its hydrochloride salt.

In another embodiment, racemic compounds of the formula C may beresolved via the selective precipitation of one of the enatiomers as itssalt with an optically enriched chiral acid, of which many examples areknown in the art, from suitable solvents, e.g. methanol and ethanol.Such optically enriched chiral acids may be naturally occuring orsynthetic. The precipitated salts may be hydrates or solvates.

In a preferred embodiment, (RS)-N-benzyl-N-methyl-2-phenylglycinamide istreated with di(o-toluoyl)-L-tartaric acid in methanol at 20° C. Theprecipitated salt is filtered and washed with methanol, then driedproviding (S)-N-benzyl-N-methyl-2-phenylglycinamidedi(o-toluoyl)-L-tartrate with 92.7% d.e. (chiral HPLC). This material isreslurried in hot methanol, filtered, washed and dried to providing(S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with99% d.e. (37% overall yield).

The diastereomericly enriched salts formed as described in the previousembodiments may be broken to provide optically enriched free amines C,e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamide, which may beadvantageously purified by crystallization as-is or by the formation ofa salt with an achiral acid in the presence of suitable solvents, e.g.precipitation of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloridefrom mixtures of propan-2-ol and tert-butyl methyl ether.

In another embodiment, a racemic compound of the formula C may beresolved via the selective recrystallization of its salt with anoptically enriched chiral acid, e.g.(RS)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrateprepared as described above, from a suitable solvent, to providediastereomericly enriched salts, e.g.(S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate.Breakage of these salts delivers optically enriched free amines of theformula, C, which may be advantageously isolated and used as thehydrochloride salt, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamidehydrochloride.

In another embodiment, where optically enriched compunds C arepreferred, the unwanted enantiomer of the compound C may be recycled byracemization. In a more preferable embodiment, the racemization isapplied to mother liquors from the resolutions described above byrefluxing in the presence of a catalytic amount of a carbonyl compound,e.g. 2-chlorobenzaldehyde, thus allowing the isolation of second cropsof diastereomerically enriched salts containing the desired enatiomer ofcompound C, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamidedi(o-toluoyl)-L-tartrate with 92% d.e. in approximately 50% yield of thesolute in the initial ethanolic mother liquors. In a still morepreferred embodiment, the catalysed racemization is performed at asuitable temperature and concentration in-situ during the resoluton in asuitable solvent, prior to the isolation of the first crop of product;this “dynamic resolution” allows a first crop yield of product to besignificantly greater than the 50% available by traditional saltresolutions. Dynamic resoultions are known in the art, but areconsidered far from trivial and highly substrate dependant.

In still another embodiment of a process for preparing an opticalyenriched compound of formula C, a homochiral amino acid, e.g.(S)-L-2-phenylglycine, is converted to the correspondingN-carboxyanhydride, e.g. (S)-4-phenyl-1,3-oxazolidine-2,5-dione, usingmethods well known in the art, which, may then be combined an amine,e.g. N-methylbenzylamine. The resulting mixture is then subjected to anaqueous work-up, providing the optically enriched aminoamide, e.g.(S)-N-benzyl-N-methyl-2-phenylglycinamide, which may be purified as-isor as a suitable salt.

The invention also relates to a process for preparing a compound offormula 2 which comprises: (a) forming an amide linkage between acompound of the formula A and a compound of the formula B2:

and (b) forming an amide linkage between the product of step (a) and acompound of the formula C; wherein R², R³, R⁹, L^(c), y and A and C areas defined above.

The invention also relates to a process for preparing a compound offormula 2 which comprises forming an amide linkage between a compound ofthe formula AB2:

and a compound of the formula C; wherein R², R³, R⁹, R¹⁰, R¹¹ and y areas defined above.

The invention also relates to a process for preparing a compound offormula 1b, wherein X¹ is S or O, which comprises: (a) forming an amidelinkage between a compound of the formula AB3:

and a compound of the formula C, wherein X¹ is S or O, and (b) formingan amide linkage between the product of step (a) and a compound of theformula C, wherein the compound of formula A and the compound of formulaC are as defined above.

The invention also relates to a process for preparing a compound offormula 1b, wherein X¹ is S or O, which comprises: (a) forming an amidelinkage between a compound of the formula B3 and a compound of theformula C; and (b) forming an amide linkage between the product of step(a) and a compound of the formula A, wherein A, B3 and C are as definedabove.

It is to be understood that the methods of preparing the compoundsdisclosed herein, including the compounds of formulas 1, 1b and 2, theirvaried embodiments and synthetic precursors or intermediates are notlimiting but only illustrative.

The compounds of this invention are useful as MTP/ApoB inhibitors.

The terms “compound(s) of formula 1”, “compound(s) of formula 1b”,“compound(s) of formula 2”, etc. include a compound of formula 1 (or 1bor 2, respectively) as defined herein and all of the embodiments,preferred embodiments, more preferred embodiments, and particularlypreferred embodiments of such compounds, including the compounds namedor exemplified herein, each of which is a particularly preferredembodiment of the compounds defined by the formulas. Reference to “acompound of the invention” is meant to encompass any of the compounds offormula 1, formula 1b or formula 2 as those terms are defined above.Accordingly, reference to “a compound of the invention” in connectionwith any of the embodiments, preferred embodiments, more preferredembodiments or particularly preferred embodiments of the compositions,processes and methods of the invention described herein, as well asembodiments relating to salts, polymorphs, solvates, hydrates, prodrugsand isotopically-labelled derivatives of the compounds of the invention,is intended to refer to any of the compounds of formula 1 (or 1b or 2respectively) as defined above, i.e., to any of the embodiments,preferred embodiments, more preferred embodiments or particularlypreferred embodiments of the compounds, especially the compounds namedor exemplified herein.

This invention also relates to the salts, polymorphs, solvates andhydrates of the compounds of the invention, as well as to the salts,polymorphs, solvates and hydrates of the synthetic precursors of each ofthe compounds of the invention. The invention relates to polymorphs ofthe compound of formula 1, wherein R¹-R⁸ are as defined above, having anX-ray powder diffraction patterns substantially the same as shown in anyof FIGS. 1, 3, 4, and 5. It is to be understood that some level of noiseis inherent in the generation of a diffraction pattern, i.e., peaks inintensity are to be discriminated from background according to methodswell-known in the art. In a preferred embodiment, the compound is(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamideand the X-ray powder diffraction pattern is substantially the same asthat shown in FIG. 1. In a more preferred embodiment, the compound hasan X-ray powder diffraction pattern having peaks at 2-theta valuessubstantially the same as the 2-theta values for at least ten of thepeaks of highest intensity in the X-ray powder diffraction pattern shownin FIG. 1.

In an embodiment, the compound of the invention is a polymorph of thecompound of formula 1 having a differential scanning calorimetry (DSC)profile substantially the same as that shown in FIG. 2. In a preferredembodiment, the compound is(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide.In a more preferred embodiment, the compound exhibits a heat absorptiononset temperature, peak temperature and characteristic shapesubstantially the same as that shown in FIG. 2.

The term “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups that maybe present in the compounds of the invention. For example,pharmaceutically acceptable salts include sodium, calcium and potassiumsalts of carboxylic acid groups and hydrochloride salts of amino groups.Other pharmaceutically acceptable salts of amino groups arehydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate,dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate,mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate)salts. The preparation of such salts is described below.

The compounds of the invention that are basic in nature are capable offorming a wide variety of salts with various inorganic and organicacids. The acids that may be used to prepare pharmaceutically acceptableacid addition salts of such basic compounds of the invention are thosethat form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The compounds of the invention that are acidic in nature, are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include the alkali metal or alkaline earth metalsalts and particularly, the sodium and potassium salts. This inventionalso encompasses pharmaceutical compositions containing, and methods oftreating proliferative disorders or abnormal cell growth throughadministering, prodrugs of compounds of the invention. Compounds of theinvention having free amino, amido, hydroxy or carboxylic groups can beconverted into prodrugs. Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compounds ofthe invention. The amino acid residues include but are not limited tothe 20 naturally occurring amino acids commonly designated by threeletter symbols and also includes 4-hydroxyproline, hydroxylysine,demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline homocysteine, homoserine, omithineand methionine sulfone. Additional types of prodrugs are alsoencompassed. For instance, free carboxyl groups can be derivatized asamides or alkyl esters. Free hydroxy groups may be derivatized usinggroups including but not limited to hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs ofhydroxy and amino groups are also included, as are carbonate prodrugs,sulfonate esters and sulfate esters of hydroxy groups. Derivatization ofhydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein theacyl group may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in J. Med. Chem. 1996, 39, 10. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities.

In certain combination therapies with other lipid-lowering agents, suchas those described hereinbelow, e.g., HMG CoA reductase inhibitors, HMGCoA synthetase inhibitors, ACAT inhibitors, squalene synthetaseinhibitors, etc., a compound of the invention may further comprise aprodrug which comprises a compound of formula 1 in a hydrolyzablelinkage to another anti-cancer agent. Di-ester linkages, for example,are particularly useful for this purpose, i.e., the prodrug is in theform A¹-C(O)O-L¹-O(O)C-A², wherein A¹ and A² are the two agents, L¹ is alinker such as a methylene or other (C₁-C₆) alkylene group (alone orfurther comprising a phenyl or benzyl group). The two agents may both bea compound of the invention, or one may be another agent useful fortreating, e.g., obesity, as described herein. See, e.g., U.S. Pat. No.4,342,772—penicillins in di-ester linkages with β-lactamase inhibitors.Accordingly, a compound of the invention having an available carboxylicacid group provides just one convenient means of producing combinationprodrugs of the compound of the invention, which are encompassed by thisinvention. Typically, the acidic conditions of the gastrointestinaltract, or enzymes localized in the cells thereof cause the hydrolysis ofthe prodrug, releasing both agents.

Certain compounds of the invention have asymmetric centers and thereforeexist in different enantiomeric forms. All optical isomers andstereoisomers of the compounds of the invention, and mixtures thereof,are considered to be within the scope of the invention. With respect tothe compounds of the invention, this invention includes the use of aracemate, one or more enantiomeric forms, one or more diastereomericforms, or mixtures thereof. Some of the compounds of the invention mayalso exist as tautomers, including, e.g., keto-enol tautomers. Thisinvention relates to the use of all such tautomers and mixtures thereof.

Furthermore, some compounds may exhibit polymorphism. It is to beunderstood that the present invention encompasses any and all racemic,optically-active, polymorphic and stereoisomeric forms, or mixturesthereof, which form or forms possess properties useful in the treatmentof the conditions noted hereinabove, it being well known in the art howto prepare optically-active forms (for example, by resolution of theracemic form by recrystallization techniques, by synthesis fromoptically-active starting materials, by chiral synthesis, or bychromatographic separation using a chiral stationary phase) and how todetermine efficacy for the treatment of the conditions noted herein bythe standard tests described hereinafter.

The subject invention also relates to isotopically-labelled compounds ofthe invention which are identical to those recited in formula 1, formula1b and formula 2 but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Compounds of the invention and pharmaceutically acceptablesalts of said compounds which contain the aforementioned isotopes and/orother isotopes of other atoms are within the scope of this invention.Certain isotopically-labelled compounds of the present invention, forexample those into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labelled compounds of this invention can generally beprepared by carrying out the procedures disclosed in the Schemes and/orin the Examples below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

The following selected functional group definitions and examples thereofare employed throughout the instant specification and the appendantclaims and are offered by way of illustration, and not by limitation.

The term “alkyl” means both straight and branched chain saturatedhydrocarbon groups. Some examples of alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term “cycloalkyl” means both straight and branched chain saturatedhydrocarbon groups comprising at least one ring or cyclic structure, andunless otherwise specified, is monocyclic. Some examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Someexamples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “bicycloalkyl” means both straight and branched chain saturatedhydrocarbon groups, optionally containing one or more double or triplebonds, comprising at least two rings or cyclic structures, which cyclicstructures may contain one or more common carbon atoms, i.e.,encompasses bridged bicyclic and spiro-bicyclic groups. Bicycloalkylgroups preferably contain from 5 to 12 members, more preferably, from 6to 10 members. Preferably, each ring of a bicycloalkyl group containsfrom 3 to 6 members. An example of a bicycloalkyl group isspiro[4.5]decyl. In this application, the term “bridged” when referringto any bicyclic group means that the two rings share at least two commonatoms; the shared atoms are known in the art as “bridgehead” atoms.Spiro bicyclic groups, in contrast, are bicyclic groups whose two ringsshare only a single bridgehead atom. Some other examples of bicycloalkylgroups are norbornyl, norbornenyl, bicyclo[3.1.0]hexyl. Bicycloalkylgroups may be in any available conformation, e.g., cis, trans, endo, exowith respect to their linkage to other groups or with respect to theirsubstituents.

The term “alkenyl” means both straight and branched chain unsaturatedhydrocarbon groups containing at least two carbons. Some examples ofalkenyl groups are ethenyl, propenyl and isobutenyl.

The term “alkynyl” means both straight and branched chain hydrocarbongroups containing at least one triple bond between two carbon atoms.Some examples of alknyl groups are ethynyl and propynyl, e.g.,propyn-1-yl and propyn-2-yl and propyn-3-yl.

The term “alkoxy” means a straight or branched chain hydrocarbon groupattached through an oxygen atom. Some examples of alkoxy groups aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexoxyand heptoxy.

The term “acyl” means either a straight or branched chain hydrocarbonmoiety attached through a carbonyl group. Some examples of acyl groupsare acetyl, propionyl, butyryl and isobutyryl.

The terms “halogen” or “halo” mean fluoro, chloro, bromo, and iodogroups, unless specified otherwise.

The term “haloalkyl”, as used herein, unless otherwise indicated, meansan alkyl group substituted with one or more halo groups, on one or morecarbon atoms. Preferably, the haloalkyl comprises 1 to 3 halo groups,such as a hydrocarbon comprising a dichloromethyl group, or amonohalosubstituted hydrocarbon.

The term “perfluoro”, when used in conjunction with a specifiedhydrocarbon group, is meant to include a substituent wherein theindividual hydrogen atoms thereof are substituted therefor with fluorineatoms, preferably, wherein all the individual hydrogen atoms thereof aresubstituted therefor with fluorine. Some examples of perfluoro groupsare trifluoromethyl (perfluoromethyl), pentafluoroethyl (perfluoroethyl)and heptafluoropropyl (perfluoropropyl).

The term “alkoxycarbonyl” means an alkoxy group attached through acarbonyl group. Some examples of alkoxycarbonyl groups aremethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl andbutoxycarbonyl.

The term “alkylthio” means an alkyl group attached through a sulfuratom. Some examples of alkylthio groups are methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, pentylthio andhexylthio.

The term “alkylamino” means an alkyl group attached through a nitrogenatom, wherein the nitrogen is unsubstituted, i.e., the group isalkyl-NH—. Some examples of alkylamino groups are methylamino,ethylamino, propylamino, isopropylamino, butylamino and isobutylamino.

The term “dialkylamino” means an alkylamino group wherein the nitrogenatom is substituted with two independent alkyl groups R^(a) and R^(b),i.e., —N(R^(a)R^(b)). Some examples of dialkylamino groups aredimethylamino, diethylamino, dipropylamino and di-isopropylamino as wellas N-methyl-N′-ethylamino, N-ethyl-N′-propylamino andN-propyl-N′-isopropylamino.

Some examples of acyloxy groups include acetyloxy, propionyloxy,butyryloxy, and also include such radicals which incorporate a cyclicsubstituent such as benzoyloxy.

The term “haloalkoxy”, as used herein, unless otherwise indicated, meansan —O-haloalkyl group wherein “haloalkyl” is as defined above. Anexample of a haloalkoxy group is trifluoromethoxy.

The term “aryl”, as used herein, unless otherwise indicated, means anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl. Aryl is most preferably phenyl. Itis to be understood that a napthyl group may be bonded through anyposition, i.e., napth-1-yl, napth-2-yl, napth-3-yl, napth-4-yl.

The terms “heterocyclyl” and “heterocyclic”, as used herein, unlessotherwise indicated, mean non-aromatic (saturated or unsaturated)monocyclic and multicyclic groups containing one or more heteroatomseach selected from O, S and N, wherein each ring of a heterocyclic grouphas from 3 to 8 atoms. Preferably, heterocyclic groups of this inventionare monocyclic or bicyclic.

Monocyclic heterocyclic groups include rings having only 4 atoms;preferably, monocyclic heterocyclic groups contain from 4 to 8 members,and more preferably, from 4 to 6 members, and most preferably, 5 or 6members. An example of a 4-membered heterocyclic group is azetidinyl(derived from azetidine), an example of a 5-membered heterocyclic groupis imidazolidinyl, and an example of a 6-membered heterocyclic group ispiperidinyl. Other examples of monocyclic heterocyclic groups arepyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl,piperazinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolinyl, 2H-pyranyl,4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, pyrazolinyl,pyrazolidinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl andimidazolinyl. Other examples of monocyclic heterocyclic groups includeazacycloheptane and azacyclooctane. Preferred monocyclic heterocyclicgroups are azetidinyl, pyrrolidinyl, piperidinyl and morpholino.Monocyclic heterocyclic groups may be referred to herein as“heteromonocyclyl.”

Bicyclic heterocyclic groups may be referred to herein as“heterobicyclic” or “heterobicyclyl”, both of which as used herein meanheterocyclic groups containing two rings, and encompass fused-ringbicyclic, bridged bicyclic and spiro-bicyclic groups. Heterobicyclicgroups preferably contain from 5 to 12 members, more preferably, from 6to 10 members. Preferably, each ring of a heterobicyclic group containsfrom 3 to 6 members. An example of a heterobicyclic group is1,4-dioxaspiro[4.5]decyl. Some other examples of heterobicyclic groupsinclude azabicyclohexyl, e.g., 3-azabicyclo[3.1.0]hexyl,azabicycloheptyl, e.g., 2-azabicyclo[2.2.1]heptyl and azabicyclooctyl.

The term “heteroaryl” as used herein means aromatic heterocyclic groupscomprising from 5 to 12 atoms and containing one or more heteroatomseach selected from O, S and N, wherein each ring of the heteroaryl groupcontains from 3 to 8 atoms. Heteroaryl groups of this invention unlessotherwise indicated may contain one ring or more than one ring, i.e.,they may be monocyclic or multicyclic, for example bicyclic, so long asat least one ring in a multicyclic group is aromatic. Preferably,heteroaryl groups of this invention are monocyclic or bicyclic.Preferably, each ring of a heteroaryl group contains one or twoheteroatoms. Monocyclic heteroaryl groups preferably contain from 5 to 8members, more preferably, 5 or 6 members. Preferably, the monocyclicheteroaryl groups containing two heteratoms contain two nitrogen atoms,a nitrogen atom and an oxygen atom, or a nitrogen atom and a sulfuratom. Some examples of monocyclic heteroaryl groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thiophenyl (referred to hereinafter as “thienyl”), isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyland furazanyl (i.e., 2,5-diaza-furanyl). Preferred among the monocyclicheteroaryl groups are thienyl, furyl and pyridinyl. More preferredmonocyclic heteroaryl groups are thien-2-yl, fur-2-yl, pyridin-2-yl,pyridin-3-yl, i.e., attached through the 2- or 3-carbon, respectively. Aparticularly preferred monocyclic heteroaryl group is pyridyl. The term“pyridyl” as used in this application, unless otherwise specified, means2-pyridyl, 3-pyridyl or 4-pyridyl, i.e., pyridyl attached through anyavailable carbon atom.

Multicyclic heteroaryl groups are preferably bicyclic; bicyclicheteroaryl groups preferably contain 9 or 10 members. Some examples ofheteroaryl groups are quinolinyl, isoquinolinyl, indolyl, 3H-indolyl,indolinyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzisothiazolyl,benzoxazolyl, pteridinyl, benzothiadiazine, benzothiazinyl,2H-1-benzopyranyl, chromanyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl.

The foregoing heterocyclic and heteroaryl groups may be C-attached orN-attached where such is possible. For instance, pyrrolyl may bepyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). The heterocyclicgroups of this invention also include ring systems substituted with oneor more oxo moieties.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating, as“treating” is defined immediately above.

The invention further relates to a pharmaceutical composition comprisinga compound of formula 1 and a pharmaceutically acceptable carrier. Thepharmaceutical composition may, for example, be in a form suitable fororal administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired. Aqueous compositions of thepresent invention may comprise other pharmaceutically acceptable solutesincluding additives and other therapeutic agents, as appropriate.Suitable additives are those well known in the art including, but notlimited to, antioxidants, antibacterials, surfactants, chelating agents,sugars, and preservatives. Aqueous compositions of the invention can beadministered by injection, which can be intramuscular, intravenous orpreferably subcutaneous. A dose of from about 0.5 μg/Kg/day to about 10μg/Kg/day, preferably from about 1 μg/Kg/day to 5 μg/Kg/day, can beused.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington: The Practice ofPharmacy, Lippincott Williams and Wilkins, Baltimore Md., 20^(th) ed.2000.

The compounds of the invention can be administered alone but willgenerally be administered in an admixture with suitable pharmaceuticalexcipient(s), diluent(s) or carrier known in the art and selected withregard to the intended route of administration and standardpharmaceutical practice. If appropriate “auxiliary” agents may also beadded, which includes preservatives, anti-oxidants, flavors orcolorants. The compound of the invention may be formulated to provideimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release dependent on the specific route of administration andthe specificity of release profile, commensurate with therapeutic needs.

The compounds of the invention can be administered, for example but notlimited to, the following route: oral (including buccal, sublingual,etc.) in the forms that are well known in the art (ref.) for veterinaryand pharmaceutical applications. “Oral” in this instance refers to oralmode of administration wherein the forms are explicitly provided to theanimals for oral consumption i.e., on-diet, in-drinking fluid, placeddirectly into the oral cavity, or offered for free-choice consumption.In this invention, the term “animal” includes a warm-blooded animal ofthe animal kingdom possessed of a homeostatic mechanism and includesmammals and birds, preferably companion animals and livestock animals,and humans. Some examples of companion animals are canines, e.g., dogs,felines, e.g., cats and horses; some examples of livestock animals arepigs, cows, sheep and the like. Preferably, the animal is a mammal. Morepreferably, the mammal is a companion animal or a livestock animal.

Typical oral solid forms may include tablets, powders, multi-particulatepreparations (granules), capsules, chews, lozenges, films, patches, etc.Typical oral liquid (including semi-solid and colloidal) forms mayinclude solutions, elixirs, gels, sprays, liquid-filled chews, etc.Other oral forms wherein the active agent is suspended in a liquid orsemi-solid carrier phase, for example suspensions, may also be used.

The preferred oral solid, liquid and suspension forms for a compound ofthe invention are those that impart flexibility in dosing to theanimals, wherein the method of administration is facile and the dose canbe accurately and flexibly controlled in keeping with the need of thetherapy. Examples of such forms include tablet preparations, solutions(and similar forms thereof as described herein) and suspensions. Inthese examples, the dose can be easily controlled for oraladministration. Particularly for solutions and suspensions, the utilityof appropriate metering systems (i.e., calibrated syringes etc.)provides high flexibility in controlling the dose to facilitateadministration to animal species of different sizes or to differentanimal species or breeds, with varying dose requirements. Additionally,the utility of flavoring/palatability agents and/or texture enhancers inthe said forms can promote animal acceptance and compliance, which canbe particularly advantageous when dosing chronically to animals.

The compounds of the invention may also be administered via theparenteral routes. The term parenteral in this context refers to allroutes of drug administration that is not via the oral cavity.Preferably for the compounds of the innovation, parenteral routes mayinclude topical and transdermal, rectal, vaginal, nasal, inhalation andinjectables (i.e., administration modes that require penetration of theskin barrier via needle and needle-less methods, including implants andreservoirs). Formulations for these routes of administration may beprepared in a conventional manner in accordance with standardpharmaceutical and veterinary practices, illustrative examples of whichare described herein.

Particularly preferred compositions of the compounds of the inventioncomprise oral solid forms, examples of which are provided below, arepreferably tablets, powders or granules which typically contain just theactive agent(s) or preferably in combination with adjuvants/excipients.

In an embodiment of the invention, the pharmaceutical compositioncomprises a compound the invention, herein referred to also as “theactive” in an amount typically less than 50% (by weight) of theformulation and preferably less than 10%, more preferably, about 2.5% byweight, and a pharmaceutically acceptable carrier. In a preferredembodiment, the predominant portion of the formulation comprisesfillers, diluents, disintegrants, lubricants and optionally, flavors.The composition of these excipients is well known in the art. In anembodiment of the invention, the preferred fillers/diluents compriseadmixtures of two or more of the following components: avicel, mannitol,lactose (all types), starch, and di-calcium phosphate. In preferredembodiments of the compositions, the filler/diluent admixtures typicallycomprises less than 98% (by weight) of the formulation and preferablyless than 95%, for example 93.5%. In a preferred embodiment,disintegrants include Ac-di-sol, Explotab™, starch and sodium laurylsulphate (SLS)—also known as wetting agent. In a more preferredembodiment, the amount of filler/diluent admixture usually comprisesless than 10% (by weight) of the composition and preferably less than5%; in a particularly preferred embodiment, the amount is about 3%. In aparticularly preferred embodiment, the lubricant is magnesium stearate.In preferred embodiments thereof, the magnesium stearate is present inan amount less than about 5% of the formulation and preferably less thanabout 3%, more preferably, about 1%. Preferably, lubricants compriseless than 60% of the formulation, preferably less than 40%, and mostpreferably, from about 10% to about 20%. Particularly preferredembodiments of tablet formulations for the compounds of the inventionare shown in Table 10.

The compositions of the invention include tablets. In a preferredembodiment, tablets are manufactured by a process selected from directcompression or a wet, dry or melt granulation, melt congealing processand extrusion. In another embodiment, tablet cores of the compositionsof the invention may be mono or multi-layer(s) and can be coated withappropriate overcoats known in the art.

Oral liquid forms of the compounds of the invention are preferablysolutions, wherein the active compound is fully dissolved. In anembodiment, the solution comprises the active and a pharmaceuticallyprecedented solvents suitable for oral administration. In a preferredembodiment, the solvent is one in which the compounds of the inventionshow good solubility. In a more preferred embodiment, the solutioncomprises a solvent selected from polyethylene glycol, polypropyleneglycol, edible oils and glyceryl- and glyceride-based systems. In morepreferred embodiments, glyceryl- and glyceride-based systems compriseagents selected from Captex 355 EP, Crodamol GTC/C, or Labrafac CC,triacetin, Capmul CMC, Migyols (812, 829, 840), Labrafil M1944CS, Peceoland Maisine 35-1. The exact composition of these agents and commercialsources are shown in Table 11. These solvents usually make up thepredominant portion of the formulation i.e., greater than 50% (byweight) and preferably greater than 80%, for example 95% and morepreferably greater than 99%. In preferred embodiments, the solutionfurther comprises an adjuvant or additives. In a preferred embodimentthereof, the additive or adjuvant is a taste-mask agent, palatabilityagent, flavoring agent, antioxidant, stabilizer, texture modifier,viscosity modifier, or a solubilizer.

A further embodiment is a process for preparing preferred oral liquidform of the compounds of the invention (see the PharmaceuticalCompositions section), wherein the individually preferred components arecombined optionally with mechanical or ultrasonic agitation in apreferred temperature range, in such a fashion that is advantageous tothe rate of dissolution.

The compounds of the instant invention inhibit or decrease Apo Bsecretion, likely by the inhibition of MTP, although it may be possiblethat other mechanisms are involved. The compounds are useful in treatingany of the disease states or conditions in which Apo B, serumcholesterol, and/or triglyceride levels are elevated. Thus, thecompositions of this invention are useful for the treatment ofconditions including atherosclerosis, pancreatitis, obesity,hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and diabetes.Accordingly, this invention provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of theinvention, including the stereoisomers, pharmaceutically acceptablesalts and solvates thereof, in combination with a pharmaceuticallyacceptable carrier or diluent.

The instant invention also relates to a method for inhibiting ordecreasing Apo B secretion in an animal in need thereof which comprisesthe administration of an Apo B secretion inhibiting or decreasing amountof a compound of the invention or a stereoisomer, pharmaceuticallyacceptable salt or solvate thereof. The invention further provides amethod of treating a condition selected from atherosclerosis,pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia,hyperlipidemia, and diabetes which comprises administering to an animalin need of such treatment a therapeutically effective amount of acompound of formula 1 (or 1b or 2) or a stereoisomer, pharmaceuticallyacceptable salt or solvate thereof. A preferred subgroup of theconditions described hereinabove is atherosclerosis, obesity,hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, anddiabetes.

In one aspect, the present invention concerns the treatment of diabetes,including impaired glucose tolerance, insulin resistance, insulindependent diabetes mellitus (Type I) and non-insulin dependent diabetesmellitus (NIDDM or Type II). Also included in the treatment of diabetesare the diabetic complications, such as neuropathy, nephropathy,retinopathy or cataracts.

Diabetes can be treated by administering to an animal having diabetes(Type I or Type II), insulin resistance, impaired glucose tolerance, orany of the diabetic complications such as neuropathy, nephropathy,retinopathy or cataracts, a therapeutically effective amount of acompound of the present invention. It is also contemplated that diabetesbe treated by administering a compound of the invention along with otheragents that can be used to treat diabetes. Preferably, the diabetes isType II diabetes. More preferably, the animal is feline; even morepreferably, the feline is a cat.

Accordingly, this invention further relates to a method of treating TypeII diabetes in an animal in need of such treatment, which comprisesadministering to the animal a therapeutically effective amount of acompound of formula 1 or a stereoisomer, pharmaceutically acceptablesalt or solvate thereof.

The invention also provides a method of treating Type II diabetes in ananimal in need of such treatment, which comprises administering to theanimal a therapeutically effective amount of a compound of formula 1 ora stereoisomer, pharmaceutically acceptable salt or solvate thereof, incombination with one or more additional agents capable of treating TypeII diabetes in the animal.

Representative agents that can be used to treat diabetes include insulinand insulin analogs (e.g. LysPro insulin); GLP-1 (7-37) (insulinotropin)and GLP-1 (7-36)-NH₂; sulfonylureas and analogs: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, Glypizide®,glimepiride, repaglinide, meglitinide; biguanides: metformin,phenformin, buformin; α2-antagonists and imidazolines: midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, A-4166; glitazones: ciglitazone,pioglitazone, englitazone, troglitazone, darglitazone, BRL49653; fattyacid oxidation inhibitors: clomoxir, etomoxir; α-glucosidase inhibitors:acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose,MDL-73,945; β-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL316,243; phosphodiesterase inhibitors: L-386,398; lipid-lowering agents:benfluorex; antiobesity agents: fenfluramine and orlistat; vanadate andvanadium complexes (e.g. Naglivan®) and peroxovanadium complexes; amylinantagonists; glucagon antagonists; gluconeogenesis inhibitors;somatostatin analogs; antilipolytic agents: nicotinic acid, acipimox,WAG 994; and glycogen phosphorylase inhibitors, such as those disclosedin WO 96/39385 and WO 96/39384. Also contemplated in combination withcompounds of the invention are pramlintide acetate (Symlin™) andnateglinide. Any combination of agents can be administered as describedabove.

The invention also relates to a method of treating obesity in a mammalwhich comprises administering to an animal in need of such treatment aneffective amount of an intestinal-MTP-selective compound, wherein theED₂₅ of the compound for the inhibition of intestinal fat absorption isat least 5-fold lower than the ED₂₅ of the compound for the lowering ofserum triglycerides. In an embodiment, the ED₂₅ for the inhibition ofintestinal fat absorption is at least 10-fold lower than the ED₂₅ of thecompound for the lowering of serum triglycerides. In another embodiment,the compound exhibits an ED₂₅ for the inhibition of intestinal fatabsorption which is at least 50-fold lower than the ED₂₅ of the compoundfor the lowering of serum triglycerides.

In another embodiment, the intestinal-MTP-selective compound is acompound of formula 1, 1b or 2, or an embodiment, preferred embodiment,more preferred embodiment, or particularly preferred embodiment of acompound of formula 1, 1b or 2.

In this invention, the term “selectivity” refers to a greater effect ofa compound in a first assay, compared to the effect of the same compoundin a second assay. In the above embodiment of the invention, the firstassay is for the ability of the compound to inhibit intestinal fatabsorption and the second assay is for the ability of the compound tolower serum triglycerides. In a preferred embodiment, the ability of thecompound to inhibit intestinal fat absorption is measured by the ED₂₅ ofthe compound in an intestinal fat absorption assay, such that a greatereffect of the compound results in the observation of a lower absolute(numerical) value for the ED₂₅. In another preferred embodiment, theability of the compound to lower serum triglycerides is measured by theED₂₅ of the compound in a serum triglyceride assay. Again, a greatereffect of a compound in the serum triglyceride lowering assay results inthe observation of a lower absolute (numerical) value for the ED₂₅. Anillustrative example of each assay is provided hereinbelow, but it is tobe understood that any assay capable of measuring the effectiveness of acompound in inhibiting intestinal fat absorption, or capable ofmeasuring the effectiveness of a compound in lowering serumtriglycerides, is encompassed by the present invention.

In a particularly preferred embodiment, the intestinal-MTP-selectivecompound is a compound of formula 1b, wherein X¹ is N(R⁴) or O, X² isC(H); m, n and p are all 0; R³ is H or Cl; R⁴ is CH₃; R⁵ and R⁹ are bothH; R¹⁰ is phenyl (with carbons numbered 1′-6′) substituted at the4′-position with CF₃, or R¹⁰ is (C₁-C₆)alkoxy; R⁶ is H or methyl and R⁷is (C₁-C₆)alkyl or benzyl, wherein the benzyl is optionally substitutedwith (C₁-C₆)alkyl or (C₁-C₆)alkoxy.

The compounds of this invention may be used in conjunction with otherpharmaceutical agents, including other lipid lowering agents. Suchagents include, for example, cholesterol biosynthesis inhibitors andcholesterol absorption inhibitors, especially HMG-CoA reductaseinhibitors and HMG-CoA synthase inhibitors; HMG-CoA reductase geneexpression inhibitors; CETP inhibitors; bile acid sequestrants;fibrates; cholesterol absorption inhibitors; ACAT inhibitors, squalenesynthetase inhibitors, ion-exchange resins, anti-oxidants and niacin. Incombination therapy treatment, the compounds of the instant inventionand the other drug therapies may be administered to animals (e.g.humans) by conventional methods.

This invention provides a method of treating atherosclerosis;pancreatitis secondary to hypertriglyceridemia; hyperglycemia (1) bycausing a reduced absorption of dietary fat through MTP inhibition, (2)by lowering triglycerides through MTP inhibition or (3) by decreasingthe absorption of free fatty acids through MTP inhibition; in an animalin need of treatment thereof, which comprises administering to theanimal a therapeutically effective amount of the compound of formula 1,1b or 2.

The invention also provides a pharmaceutical composition comprising: a)a therapeutically effective amount of a first compound, wherein saidfirst compound is a compound of claim 1 or a stereoisomer,pharmaceutically acceptable salt or hydrate thereof; b) atherapeutically effective amount of a second compound, wherein saidsecond compound is selected from a cholesterol absorption inhibitor, aCETP inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthaseinhibitor, an inhibitor of HMG-CoA reductase gene expression, niacin, anantioxidant, an ACAT inhibitor or a squalene synthetase inhibitor; andc) a pharmaceutically acceptable carrier or diluent. In a preferredembodiment of the invention, the said second compound is selected fromlovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin orrivastatin. In a more preferred embodiment of the invention, said secondcompound is atorvastatin.

Specific cholesterol absorption inhibitors and cholesterol biosynthesisinhibitors are described in detail hereinbelow. Additional cholesterolabsorption inhibitors are known to those skilled in the art and aredescribed, for example, in PCT WO 94/00480.

Any HMG-CoA reductase inhibitor may be employed as the second compoundin the combination therapy aspect of the instant invention. The termHMG-CoA reductase inhibitor refers to a compound which inhibits thebiotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acidas catalyzed by the enzyme HMG-CoA reductase. Such inhibition may bedetermined readily by one of skill in the art according to standardassays (e.g., Methods of Enzymology, 1981; 71: 455-509 and thereferences cited therein). A variety of these compounds are describedand referenced hereinbelow. U.S. Pat. No. 4,231,938 (the disclosure ofwhich is hereby incorporated by reference) discloses certain compoundsisolated after cultivation of a microorganism belonging to the genusAspergillus, such as lovastatin. Also, U.S. Pat. No. 4,444,784 (thedisclosure of which is hereby incorporated by reference) disclosessynthetic derivatives of the aforementioned compounds, such assimvastatin. Additionally, U.S. Pat. No. 4,739,073 (the disclosure ofwhich is hereby incorporated by reference) discloses certain substitutedindoles, such as fluvastatin. Further, U.S. Pat. No. 4,346,227 (thedisclosure of which is hereby incorporated by reference) disclosesML-236B derivatives, such as pravastatin. In addition, EP 491,226teaches certain pyridyldihydroxyheptenoic acids, such as rivastatin.Also, U.S. Pat. No. 4,647,576 (the disclosure of which is herebyincorporated by reference) discloses certain6-[2-(substituted-pyrrol-1-yl)alkyl]-pyran-2ones such as atorvastatin.Other HMG-CoA reductase inhibitors will be known to those skilled in theart.

Any HMG-CoA synthase inhibitor may be used as the second compound in thecombination therapy aspect of this invention. The term HMG-CoA synthaseinhibitor refers to a compound which inhibits the biosynthesis ofhydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A andacetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Suchinhibition may be determined readily by one of skill in the art according to standard assays (e.g., Methods of Enzymology, 1975; 35:155-160 and Methods of Enzymology, 1985; 110: 19-26 and the referencescited therein). A variety of these compounds are described andreferenced hereinbelow. U.S. Pat. No. 5,120,729 (the disclosure of whichis hereby incorporated by reference) discloses certain beta-lactamderivatives. U.S. Pat. No. 5,064,856 (the disclosure of which is herebyincorporated by reference) discloses certain spiro-lactone derivativesprepared by culturing the microorganism MF5253. U.S. Pat. No. 4,847,271(the disclosure of which is hereby incorporated by reference) disclosescertain oxetane compounds such as11-(3hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undecadienoicacid derivatives. Other HMG-CoA synthase inhibitors will be known tothose skilled in the art.

Any compound that decreases HMG-CoA reductase gene expression may beused as the second compound in the combination therapy aspect of thisinvention. These agents may be HMG-CoA reductase transcriptioninhibitors that block the transcription of DNA or translation inhibitorsthat prevent translation of mRNA coding for HMG-CoA reductase intoprotein.

Such inhibitors may either affect transcription or translation directly,or may be biotransformed into compounds that have the aforementionedattributes by one or more enzymes in the cholesterol biosyntheticcascade or may lead to the accumulation of an isoprene metabolite thathas the aforementioned activities. Such regulation is readily determinedby those skilled in the art according to standard assays (Methods ofEnzymology, 1985; 110: 9-19). Several such compounds are described andreferenced below however other inhibitors of HMG-CoA reductase geneexpression will be known to those skilled in the art U.S. Pat. No.5,041,432 (the disclosure of which is incorporated herein by reference)discloses certain 15-substituted lanosterol derivatives. Otheroxygenated sterois that suppress the biosynthesis of HMG-CoA reductaseare discussed by E. I. Mercer (Prog. Up. Res., 1993; 32: 357-416).

Any compound having activity as a CETP inhibitor can serve as the secondcompound in the combination therapy aspect of the instant invention. Theterm CETP inhibitor refers to compounds which inhibit the cholesterylester transfer protein (CETP) mediated transport of various cholesterylesters and triglycerides from high density lipoprotein (HDL) to lowdensity lipoprotein (LDL) and very low density lipoprotein (VLDL). Avariety of these compounds are described and referenced hereinbelowhowever other CETP inhibitors will be known to those skilled in the artU.S. Pat. No. 5,512,548 (the disclosure of which is incorporated hereinby reference) discloses certain polypeptide derivatives having activityas CETP inhibitors, while certain CETP-inhibitory rosenonolactonederivatives and phosphate-containing analogs of cholesteryl ester aredisclosed in J. Antibiot., 1996; 49(8): 815-816, and Bioorg. Med. Chem.Lett; 1996; 6: 1951-1954, respectively.

Any ACAT inhibitor can serve as the second compound in the combinationtherapy aspect of this invention. The term ACAT inhibitor refers tocompounds which inhibit the intracellular esterification of dietarycholesterol by the enzyme acyl CoA:cholesterol acyltransferase. Suchinhibition may be determined readily by one of skill in the artaccording to standard assays, such as the method of Heider et al.described in Journal of Lipid Research., 1983; 24: 1127. A variety ofthese compounds are described and referenced hereinbelow however otherACAT inhibitors will be known to those skilled in the art.

U.S. Pat. No. 5,510,379 (the disclosure of which is incorporated byreference) discloses certain carboxysulfonates, while WO 96/26948 and WO96/10559 both disclose urea derivatives having ACAT inhibitory activity.

Any compound having activity as a squalene synthetase inhibitor canserve as the second compound in the combination therapy aspect of theinstant invention. The term squalene synthetase inhibitor refers tocompounds that inhibit the condensation of two molecules offarnesylpyrophosphate to form squalene, a reaction that is catalyzed bythe enzyme squalene synthetase. Such inhibition is readily determined bythose skilled in the art according to standard methodology (Methods ofEnzymology 1969; 15: 393-454 and Methods of Enzymology 1985; 110:359-373 and references cited therein). A summary of squalene synthetaseinhibitors has been complied (Curr. Op. Ther. Patents (1993) 86-14).European patent application publication No. 0 567 026 A1 disclosescertain 4,1-benzoxazepine derivatives as squalene synthetase inhibitorsand their use in the treatment of hypercholesterolemia and asfungicides. European patent application publication No. 0 645 378 A1discloses certain seven- or eight-membered heterocycles as squalenesynthetase inhibitors and their use in the treatment and prevention ofhypercholesterolemia and fungal infections. European patent applicationpublication No. 0 645 377 A1 discloses certain benzoxazepine derivativesas squalene synthetase inhibitors useful for the treatment ofhypercholesterolemia or coronary sclerosis. European patent applicationpublication No. 0 611 749 A1 discloses certain substituted amino acidderivatives useful for the treatment of arteriosclerosis. Europeanpatent application publication No. 0 705 607 A2 discloses certaincondensed seven- or eight-membered heterocyclic compounds useful asantihypertriglyceridemic agents. PCT publication WO96/09827 disclosescertain combinations of cholesterol absorption inhibitors andcholesterol biosynthesis inhibitors including benzoxazepine derivativesand benzothiazepine derivatives. European patent application publicationNo. 0 071 725 A1 discloses a process for preparing certainoptically-active compounds, including benzoxazepine derivatives, havingplasma cholesterol and triglyceride lowering activities.

The present invention also provides a method of treating obesity in ananimal, which comprises administering to the obese animal a compound ofthis invention in combination with another anti-obesity agent.

The other anti-obesity agents is preferably selected from the groupconsisting of a β₃-adrenergic receptor agonist, a cholecystokinin-A(CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), asympathomimetic agent, a serotoninergic agent (such as fenfluramine ordexfenfluramine), a dopamine agonist (such as bromocriptine), amelanocyte-stimulating hormone receptor agonist or mimetic, amelanocyte-stimulating hormone receptor analog, a cannabinoid receptorantagonist, a melanin concentrating hormone antagonist, leptin, a leptinanalog, a leptin receptor agonist, a galanin antagonist, a lipaseinhibitor (such as orlistat), a bombesin agonist, a neuropeptide-Yantagonist such as NPY-1 or NPY-5, a thyromimetic agent,dehydroepiandrosterone or an analog thereof, a glucocorticoid receptoragonist or antagonist, an orexin receptor antagonist, a urocortinbinding protein antagonist, a glucagon-like peptide-1 receptor agonist,and a ciliary neurotrophic factor such as Axokine, or a humanagouti-related protein (AGRP) antagonist. Other anti-obesity agents arealso known, or will be apparent in light of this disclosure, to one ofordinary skill in the art.

Especially preferred anti-obesity agents comprise those compoundsselected from the group consisting of sibutramine, fenfluramine,dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin,phenylpropanolamine pseudoephedrine,{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}aceticacid,{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}benzoicacid,{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenyl}propionicacid, and{4-[2-(2-[6-aminopyridin-3-yl]-2(R)-hydroxyethylamino)ethoxy]phenoxy}aceticacid.

In preferred embodiments, the additional anti-obesity agent is anotherMTP/apoB inhibitor selected from the group consisting of (i) BMS-197636,also known as9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide;(ii) BMS-200150, also known as2-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-one;and (iii) BMS 201038, also known as9-[4-(4-[2-(4-trifluoromethylphenyl)benzoylamino]piperidin-1-yl)butyl]-N-2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide;and the pharmaceutically acceptable salts of (i), (ii) and (iii). Inanother embodiment, the anti-obesity agent is selected from the agentsdisclosed in European patent application publication Nos. 0 584 446 A2and 0 643 057 A1, the latter of which discloses certain compounds of theformulas:

which have utility as inhibitors of MTP, wherein the substituents listedin formula Ob1 are as defined in EP 0 643 057 A1. In another embodiment,the anti-obesity agent is selected from the agents disclosed in Europeanpatent application publication Nos. 1 099 439 A2, which disclosescertain compounds of the formula:

wherein L in formula Ob2 is as defined as in EP 1 099 439 A2.

Preferred compounds of those disclosed in 1 099 439 A2 are compoundsselected from the group consisting of4′-trifluoromethyl-biphenyl-2-carboxylicacid-(2-butyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide and4′-trifluoromethyl-biphenyl-2-carboxylicacid-(2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide.

Methods for preparing the above agents are publicly available; forexample, phentermine may be prepared as described in U.S. Pat. No.2,408,345; sibutramine may be prepared as in U.S. Pat. No. 4,929,629;orlistat may be prepared as in U.S. Pat. No. 4,598,089; fenfluramine anddexfenfluramine may be prepared as described in U.S. Pat. No. 3,198,834;bromocriptine may be prepared as described in U.S. Pat. Nos. 3,752,814and 3,752,888; and the substituted amino pyridines listed above may beprepared as described in PCT International Publication No. WO 96/35671;the disclosure of each of these publications is herein incorporated byreference.

It will be appreciated by those skilled in the art that certaincompounds of the instant invention may contain anasymmetrically-substituted carbon atom and accordingly may exist in,and/or be isolated in, optically-active and racemic forms. Furthermore,some compounds may exhibit polymorphism. It is to be understood that thepresent invention encompasses any and all racemic, optically-active,polymorphic and stereoisomeric forms, or mixtures thereof, which form orforms possess properties useful in the treatment of the conditions notedhereinabove, it being well known in the art how to prepareoptically-active forms (for example, by resolution of the racemic formby recrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase) and how to determineefficacy for the treatment of the conditions noted herein by thestandard tests described hereinafter.

The present invention may be understood more fully by reference to thedetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention. The term “compoundof formula 1”, “compound of formula 2,” as used herein, e.g., “apharmaceutical composition comprising a compound of formula 1 . . . ”encompasses in addition to their generic description of the compound,all of the embodiments, preferred embodiments, more preferredembodiments and particularly preferred embodiments of the compounds, aswell as each of the Examples described below.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the X-ray powder diffraction pattern of a sample ofpreferred Form A of the title compound described in Example 44. Detailedconditions for the preparation of the sample are provided in Example 44.The pattern was obtained on a Siemens D5000, Cu anode, variable slit,range 2-55, step size: 0.02; ambient temperature.

FIG. 2 shows the results of thermal analysis of preferred Form A of thetitle compound described in Example 44 by differential scanningcalorimetry. The peak is 144.068° C.; peak height, 3.8001 mW; peak area108.368 mJ; Delta H 37.485 J/g; Onset 133.524° C. The analysis wasperformed under nitrogen gas flow; after holding at 40° C. for 1 minute,heating from 40.00° C. to 200.00° C. at a rate of 20° C./minute. Thesample size was 2.891 mg.

FIG. 3 shows the X-ray powder diffraction pattern of a sample ofpreferred Form B of the title compound described in Example 44. Detailedconditions for the preparation of the sample are provided in Example 44.The pattern was obtained on a Siemens D5000, Cu anode, variable slit,range 2-55, step size: 0.02; ambient temperature.

FIG. 4 shows the X-ray powder diffraction pattern of a sample ofpreferred Form G of the title compound described in Example 44. Detailedconditions for the preparation of the sample are provided in Example 44.The pattern was obtained on a Siemens D5000, Cu anode, variable slit,range 2-55, step size: 0.02; ambient temperature.

FIG. 5 shows the X-ray powder diffraction pattern of a sample ofpreferred Form F of the title compound described in Example 44. Detailedconditions for the preparation of the sample are provided in Example 44.The pattern was obtained on a Siemens D5000, Cu anode, variable slit,range 2-55, step size: 0.02; ambient temperature.

FIG. 6 shows the X-ray powder diffraction pattern of a sample of theintermediate compound1-Methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid potassium salt 2.6 hydrate, prepared in Example 44 step (d)alternative C. Detailed conditions for the preparation of the sample areprovided in Example 44. The pattern was obtained on a Siemens D5000, Cuanode, variable slit, range 2-55, step size: 0.02; ambient temperature.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the compositions and methods of thepresent invention. It is to be understood that the present invention isnot limited to the specific details of the Examples provided below.

In the discussion which follows, certain common chemical and proceduralabbreviations and acronyms therefor have been employed which include: Me(methyl); Et (ethyl); EtOAc (ethyl acetate); Bn (benzyl); THF(tetrahydrofuran); DMF (dimethylformamide); BOC (tert-butyloxycarbonyl,a protecting group); DMAP (1,1′-dimethylaminopyridine), Ms(methanesulfonyl, mesyl); DIEA (diisopropylethylamine); TFA(trifluoroacetic acid); DIBAL (diisobutylaluminum hydride); PyBroP(Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate); DEAD (Diethylazodicarboxylate); Ac (acetyl); eq. (equivalent); RP (reverse phase);HPLC (high performance liquid chromatography); TLC (thin layerchromatography). Unless otherwise specified, “water” in the followingdescriptions means water which is deionized (also known as“demineralized”) or of higher purity, e.g., deionized-distilled ordeionized-multiply-distilled water. Preferably all materials will be ofat least USP grade.

The compounds of formula 1, 2 and 3 are most conveniently synthesized byemploying procedures analogous to those known in the chemical arts forthe production of similar compounds. Exemplary processes for themanufacture of compounds of formula 1 2 and 3 as defined in detailhereinabove are provided as further features of the invention and areillustrated by the following procedures in which the meanings of genericradicals are as previously defined unless otherwise qualified. Examplesof methods of preparing compounds of the present invention as describedherein are provided by Schemes 1-3 below and the description thatfollows. In the following Schemes, unless otherwise indicated,substituents R¹-R¹⁵, R^(a)-R^(c), L, X, Z¹ and Z² are as defined above.

The compounds of formulas 1, 2 and 3 are generally prepared by formingamide linkages between the groups A, B and C shown in Table 1 below,wherein in compounds of formula 1, B is B1; in compounds of formula 2, Bis B2; and in compounds of formula 3, B is B3; wherein L^(c) is acarboxylic acid or an activated form thereof as described further below,and the amide linkages are formed between the L^(c) group of A and theamino group —NHR⁹, and between the L^(c) group of B and the amine —NHR⁵of C, respectively It will be appreciated by those of skill in the artthat there are many well-known methods of forming amide linkages, andthat it is generally not important which amide linkage is formed first.Also, it will be appreciated by those of skill in the art that thegroups A, B and C are either commercially available or can readily beprepared using materials and methods which are well-known in the art, aswell as by the methods and procedures described herein. For example,compounds comprising the group A wherein X is C(R^(c)) and R¹⁰ is phenylare commercially available, e.g., 2-biphenylcarboxylic acid,4′-(methyl)-2-biphenylcarboxylic acid and4′-(trifluoromethyl)-2-biphenylcarboxylic acid. In addition, numerouspyridyl-phenyl (X is N and R¹⁰ is phenyl) and bipyridyl (X is N and R¹⁰is pyridyl) compounds are also readily obtained. Compounds of group Bare readily formed from commercially available indoles (B1, B2),benzo[b]furans (B3) or benzo[b]thiophenes (B3), as well as by themethods and procedures described herein. Compounds of group C arereadily prepared from commercially available phenyl glycines, whereinthe carbamoyl moiety C(O)NR⁶R⁷ is formed between the carboxylic acidgroup of the phenylglycine and the amine NR⁶R⁷. Exemplary procedures forforming each of these groups and the amide linkages between them areprovided in detail below. The Schemes which follow provide examples ofvarious methods of forming the compounds of formulas 1, 2 and 3 usingthe synthetic precursors discussed above.

TABLE 1 A B C

Scheme 1 illustrates a method for preparing a compound of formula 1which comprises reacting a compound of the formula AB1, with an amine ofthe formula C, or, by reacting a compound of the formula A with an amineof the formula B1C, where L^(c) is a carboxylic acid, preferably, anactivated carboxylic acid. In both cases, a compound of formula 1 isprepared by the formation of an amide linkage.

Activated carboxylic acids of the compound of formula A and AB1 arereadily formed by conventional means, for example, wherein -L^(c) is—COOH, by reacting the free acid with a carbodiimide, e.g.,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (“EDC”) or1,1′-carbonyldiimidazole (“CDI”). EDC, if used, may advantageously bepolymer-bound, as disclosed in U.S. Pat. No. 5,416,193. Preferably, theamide linkage reaction is carried out in the presence of a suitablebase. An example of a suitable base for use in the coupling reaction isa polymer bound amine, such as polymer bound morpholino-polystyrene.Preferably, the reaction is carried out in the presence of an alcohole.g., a C₁-C₄ alcohol such as methanol, ethanol, propanol, isopropanol,n-butanol or t-butanol. Alternatively, the carboxylic acid may beactivated by conversion to its corresponding acid chloride by e.g.,treatment with oxalyl chloride in methylene chloride in the presence ofa catalytic amount of DMF. Compounds A, C, AB1 and B1C, and theirsynthetic precursors and intermediates are each readily prepared usingwell-known methods for the formation of amide linkages, and also by themethods disclosed herein.

Another example of a method for forming the amide linkage between AB1and C, from the compound AB1 where LC is a carboxylic acid, is bycombining AB1, C, and PyBroP (about 1 eq) in methylene chloride,followed by the addition of diisopropylethylamine (2-3 eq) and stirringat room temperature from about 30 minutes to 24 hours. The solvent maybe evaporated and the product purified by TLC or flash chromatographyusing ethyl acetate/hexane as the eluting solvent.

Still another example of a method for forming the amide linkage betweenAB1 and C, where L^(c) is a carboxylic acid, is to first combine theacid (AB1) with N,O-dimethyl hydroxylamine hydrochloride salt and PyBroPin methylene chloride followed by addition of diisopropylethylamine andstirring for several hours. The resulting N,O-dimethyl hydroxyamide ofthe acid is purified by flash chromatography and then treated with DIBALin THF to yield the corresponding aldehyde (i.e., L^(c) is C(O)H). TheAB1 aldehyde is then suspended in methylene chloride with C and aceticacid, and after stirring for about 30 minutes, NaB(OAc)₃H and chloroformare added and the compound of formula 1 purified from the organic layer,e.g., by flash chromatography using methanol/chloroform.

The method illustrated in Scheme 1 comprising reacting a compound of theformula A with an amine of the formula B1C is advantageous in theutilization of a library of A groups, i.e., phenyl or pyridyl carboxylicacids as in Scheme 1, or other carboxylic acids. In this case, acompound of formula 1, formula 1b or formula 2 may be formed between acompound of the formula B1C and a A group or other carboxylic acid, byreacting A or the other acid with a mixture comprising B1C, EDC and DMAPin methylene chloride, preferably at room temperature, followed byaddition of N,N-dimethylethylenediamine, and subsequent purification ofthe compound of formula 1.

Scheme 2 illustrates a method of preparing compounds of formula AB1. InScheme 2, a compound of formula A is reacted with a 5-amino- or6-amino-indole of formula B1, wherein L^(e) is a carboxylic acid esterto form the compound AB1-e, followed by hydrolysis of L^(e) to form thecompound AB, bearing a carboxylic acid group L^(c), which as describedabove may be used in the method of Scheme 1 directly or in the form ofan activated acid. The group L^(e) may advantageously be —COOR^(d),wherein R^(d) is a (C₁-C₆) alkyl group or a substituted variationthereon; preferably R^(d) is methyl or ethyl, more preferably ethyl.Where -L^(c) is e.g., —COCl, i.e., an acid chloride, the reactionbetween A and B1 may be carried out in methylene chloride and pyridineor, in a preferred embodiment, as described in Example 44. AB1-e may behydrolysed (or otherwise deprotected) to form AB1 by any conventionalmeans, e.g., by addition of aqueous LiOH to a solution of the compoundin THF and methanol, or, in a preferred embodiment, as described inExample 44, wherein the compound AB1 has advantageous filtrationproperties, for example where L^(c) is —COOH and acidification isperformed at elevated temperature, and preferably where L^(c) is —COO⁻K⁺crystallizing as a 2.5 mole hydrate.

Still another embodiment of a process for making a compound of theformula 1 wherein R¹⁰ is of the formula —OR¹⁷ is shown in Scheme 3. Inthis process, an amide linkage is formed between A′B1 and C, wherein A′is analogous to the group R¹ except that R¹⁰ is, e.g., acetyl or athioester as exemplified by a compound such as acetylsalicoylchloride.In this process, a compound of the formula A′B1 is formed analogously tothe process shown in Scheme 2, by adding to a mixture comprising about 1equivalent of B1 (ester form, i.e. having “L^(e)” at the 2-position) anddiisopropylethylamine (2 eq) in methylene chloride, about one equivalentof A′, followed by hydrolysis of the ester group L^(e) of A′B1 toproduce a carboxylic acid group L^(c) and (preferably as part of thesame step) hydrolysis of the acetyl group of A′ to form an alcohol. Thealcohol/acid A′B1 is then reacted with C as described above, in thepresence of PyBroP to produce a hydroxy-substituted compound A′B1C whosehydroxyl group may then be converted to OR¹⁷ by reaction with an alcoholR¹⁷OH.

Compounds of formula A are well-known, and are readily obtainedcommercially or prepared from commercially available biphenyl, bipyridylor phenyl-pyridyl compounds substituted with at least a carboxylic acidgroup or having at least one substituent susceptible to derivatizationto a carboxylic acid group. Examples of suitable groups A and methodsfor preparing them may be found in, for example, U.S. Pat. No.6,121,283, which is herein incorporated by reference in its entirety. Aparticularly preferred group of formula A is4′-(trifluoromethyl)-2-biphenylcarboxylic acid, which is commerciallyavailable; other A groups are commercially available or readily preparedfrom commercially available analogues by means which are well-known inthe art.

Compounds of formula B1 are readily prepared from well-known orcommercially available indoles, e.g., 5-nitro or6-nitro-indole-2-carboxylic acid ethyl ester (“the indole ester”). Toprepare a group B1 wherein R⁴ is alkyl or alkoxyalkyl, the indole esterin a suitable solvent, e.g., DMF, may be treated with about oneequivalent of sodium hydride, followed by addition of a slight molarexcess of alkyl iodide or alkoxyalkyl iodide, e.g., methyl iodide,iodomethyl methyl ether, ethyl iodide, 2-iodopropane, etc., followed byquenching with acid, e.g., HCl, and suitable isolation to yield thealkyl or alkoxyalkyl indole ester. Alternatively the alkylating agentmay be an alkyl sulfonate ester, e.g. methyl tosylate, and the base maybe a inorganic salt, e.g. potassium carbonate, and the product providedby an appropriate isolation, such as described in Example 44. In yetanother embodiment, a group B1 wherein R⁴ is akyl or alkoxyalkyl andL^(c)=R⁴, may be prepared by exposing commercially available 5-nitro or6-nitro-indole-2-carboxylic acid to analogous conditions with adjustedstoichiometry.

Independently, or after alkylation of the indole ester, a compound B1wherein R³ is halogen, i.e., chloro, bromo or iodo, may be prepared bytreating the indole ester with a N-halosuccinimide in a suitablesolvent, e.g., THF, followed by neutralization and isolation.

After halogenation and/or alkylation (or alkoxyalkylation) the 5-nitroor 6-nitro group of any of the resulting indole esters (i.e., R³ is H orhalo and R⁴ is independently H, alkyl or alkoxyalkyl) may then bereduced, e.g., with hydrazine hydrate and Raney Nickel in a suitablesolvent, e.g., methanol to yield the 5-amino- or 6-amino-indole ester.Alternatively, the nitro group may be hydrogenated catalytically overpalladium based catalysts, e.g. palladium on carbon. Alternatively, thenitro group may be hydrogenated catalytically over palladium basedcatalysts. Alternatively, the nitro group may be subjected to catalytictransfer hydrogenation using palladium based catalysts and anon-gasseous hydrogen source, e.g., a salt of an amine with formic acidsuch as ammonium fomate, followed by an appropriate isolation, such asdescribed in Example 44. The 5-amino- or 6-amino-indole esters B1 mayadvantageously be isolated as their salts with strong acids, e.g.hydrochloric acid. Alternatively the 5-amino or 6-amino-indole estersmay be retained in solution for use directly in the following syntheticstep.

The 5-amino- or 6-amino-indole ester may then be reacted with a compoundof formula A as in Scheme 2 to form the compound AB1-e, wherein R⁹ ishydrogen. The amide nitrogen of AB1-e, is optionally alkylated, e.g.,free radical methylation is used to produce R⁹=methyl, preferably beforehydrolysis of the carboxylic acid ester to the corresponding2-carboxylic acid or activated acid form of the compound of formula B1used as in Scheme 1.

Compounds of formula B2 are readily prepared from well-known orcommercially available indoles, e.g., 5-nitro or 6-nitro-indole-1-aceticacid. Compounds of formula 2 are then readily prepared by forming amidelinkages between A, B2 and C using the processes described above forlinking B1 to A (or A′) and C.

Compounds of formula B3 are also readily prepared from well-known orcommercially available indoles, e.g., 5-nitro or6-nitro-benzofuran-2-carboxylic acid. The acid is first esterified, andthen the nitro group is reduced to an amine, both using conventionalmeans as described herein, and the amide linkages between A, B3 and C toform a compound of formula 1b are readily formed using the processesdescribed herein for linking B1 to A (or A′) and C.

Compounds of formula C are readily prepared by methods analogous tothose described above, by forming an amide linkage between aphenyl-glycine amino acid analogue, e.g.,

and an amine of the formula HNR⁶R⁷, wherein R^(p) is H or a protectinggroup, such as tert-butyloxycarbonyl (“BOC”). Various embodiments ofprocesses for preparing a compound of formula C have been describedabove, and illustrative examples are provided below.

One example of a process for preparing a compound of formula C, where,e.g., R⁷ is benzyl and R⁶ is methyl, involves combining commerciallyavailable (S)-N-tert-butoxycarbonyl-2-phenylglycine,1-hydroxybenzotriazole hydrate and N,N′-dicyclohexylcarbodimide indichloromethane, and after mixing, adding slowly, with stirring,N-methylbenzylamine in dichloromethane, all at 0-5° C. The resultingslurry is allowed to warm to room temperature overnight before beingfiltered and the solids washed with dichloromethane. The combinedfiltrate is preferably subjected to further washes with aqueous weakbase and then with aqueous weak acid, and finally washed with water,providing a dichloromethane solution of a phenylglycine acid amide,where the phenylglycine amino group (See Table 1, NHR⁵ of C) ist-butoxycarbonyl-protected. After purification, the phenylglycine amideis deprotected, e.g., by addition of concentrated hydrochloric acid, andthe monohydrate crystalline form of the product precipitated by theaddition of tert-butyl methyl ether and seeding, followed by washingwith tert-butyl methyl ether and drying to yield the product C withhigher optical purity than its N-protected precursor. The preferredsolid form of the product C is characterized by the XRD (X-raydiffraction) data shown in Table 12, as described below.

Table 12 shows 2-theta values for a simulated X-ray powder diffractionpattern the intermediate compound(S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride monohydratedescribed in Example 44 step (e). The data was simulated using primarydata obtained by single crystal X-ray diffraction.

2-theta angles and relative intensities were calculated from the singlecrystal structure using the ‘Diffraction-Crystal’ module [revision no.99.0102] of Cerius2 [version 4.2 Mat. Sci.]. Pertinent simulationparameters were:

-   Wavelength=1.54178 Å-   Polarisation Factor=0.5-   Crystallite Size=500×500×500 Å

Lorentzian Peak Shape

TABLE 12 2-Theta Intensity 2-Theta Intensity Angle (/°) (/%) Angle (/°)(/%) 5.673 100.00 25.654 9.48 11.359 8.38 25.699 2.71 12.848 23.6125.767 5.84 13.354 8.19 25.862 2.18 13.930 8.67 26.425 2.02 14.091 3.5726.665 3.22 15.374 3.21 26.894 2.36 15.750 3.88 27.054 4.25 16.668 16.5327.556 7.66 17.501 5.36 27.983 2.97 17.691 6.87 28.071 7.04 17.790 5.3128.547 5.53 18.073 2.47 28.763 3.60 18.886 2.17 28.771 3.31 19.361 42.5429.351 10.87 19.363 26.18 29.578 5.76 19.575 3.55 29.983 8.44 19.6332.40 30.830 8.48 19.922 3.34 31.115 9.03 20.103 15.17 31.746 4.06 20.2162.38 31.807 3.79 21.352 5.08 32.401 2.28 21.417 6.47 32.540 3.47 22.0225.00 33.326 2.08 22.750 14.75 33.802 2.28 22.817 6.19 36.240 3.98 22.8322.63 37.491 2.71 23.948 6.50 38.312 2.03 23.954 5.24 38.360 4.67 24.3222.66 39.406 2.45 24.399 3.20 39.752 3.11 24.471 5.84 40.510 2.81 24.6812.98 43.483 2.17 24.761 21.22

In another example of a process for preparing a compound of formula C,where R⁶ is methyl and R⁷ is benzyl,(RS)-N-tert-butoxycarbonyl-2-phenylglycine, commercially available orprepared from (RS)-2-phenylglycine using methods well known in the art,is combined with 1-hydroxybenzotriazole hydrate, commercially availableN-methylbenzylamine and N-[3-(dimethylamino)propyl-N′-ethylcarbodimidehydrochloride in dichloromethane and the resulting mixture stirred forabout 24 hours. The resulting mixture is subjected to an aqueous work-upsimilar to that described above, providing (tert-butyl(RS)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate, which may betreated with trifluorocaetic acid and triethylsilane in dichloromethane,followed by aqueous workup to yield(RS)-N-benzyl-N-methyl-2-phenylglycinamide.

A salt of the phenylglycine amide may be prepared, e.g., by treating theamide, e.g., ((RS)-N-benzyl-N-methyl-2-phenylglycinamide), withdi(o-toluoyl)-L-tartaric acid in a suitable solvent to provide thedi(o-toluoyl)-L-tartrate) salt. Tartrate salts of the phenylglycineamides may be broken to provide the amide, which may be purified as itshydrochloride salt.

In still another embodiment of a process for preparing a compound offormula C, commercially available (RS)-DL-2-phenylglycine is convertedto (RS)-4-phenyl-1,3-oxazolidine-2,5-dione using methods well known inthe art, which, analogous to the above examples, is then combined withcommercially available N-methylbenzylamine. The resulting mixture isthen subjected to an aqueous work-up, providing the phenylglycinamide,which may be purified as its hydrochloride salt as described.

In another embodiment, racemic compounds of the formula C may beresolved via the selective precipitation of one of the enantiomers asits salt with an optically enriched chiral acid, of which many examplesare known in the art, from suitable solvents, e.g. methanol and ethanol.Such optically enriched chiral acids may be naturally occuring orsynthetic. The precipitated salts may be hydrates or solvates. Breakageof these salts delivers optically enriched free amines of the formula C,which may be purified as-is or as a suitable salts using suitablesolvents.

In a preferred embodiment, (RS)-N-benzyl-N-methyl-2-phenylglycinamide(10.0 g) was treated with di(o-toluoyl)-L-tartaric acid (15.2 g) inmethanol (167 mL) at 20° C. The precipitated the salt was filtered andwashed with methanol, then dried providing(S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate(11.73 g, 46.6%) with 92.7% d.e. (chiral HPLC). This material (1.00 g)was reslurried in hot methanol (8.8 ml) to provide(S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with99% d.e. (0.79 g, 79% recovery) after filtration, washing and drying.The tartrate salts formed as described maybe broken to provide the freeamine of formula C, i.e. (S)-N-benzyl-N-methyl-2-phenylglycinamide,which may be advantageously purified by the formation of a salt with anachiral acid in the presence of appropriate solvents, e.g. precipitationof (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride from mixturesof propan-2-ol and tert-butyl methyl ether as described.

In another embodiment, a racemic compound of the formula C may beresolved via the selective recrystallization, from a suitable solvent,of its salt with an optically enriched chiral acid, e.g.(RS)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrateprepared as described above, to provide diastereomericly enriched salts,e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate.Breakage of these salts delivers optically enriched free amines of theformula C, which may be advantageoulsy isolated and used as thehydrochloride salt, e.g. (S)-N-benzyl-N-methyl-2-phenylglycinamidehydrochloride as described.

In another embodiment, where optically enriched compunds C arepreferrable, the unwanted enantiomer of the compound C may be recycledby racemization. In a more preferred embodiment, the racemization isapplied to mother liquors from the resolutions described in thepreceding embodiments, by (a) optionally changing the nature of thesolvent and (b) refluxing in the presence of a catalytic amount of acarbonyl compound, e.g. 2-chlorobenzaldehyde, thus allowing theisolation of second crops of diastereomericly enriched salts containingthe desired enantiomer of compound C, e.g.(S)-N-benzyl-N-methyl-2-phenylglycinamide di(o-toluoyl)-L-tartrate with92% d.e. in approximately 50% yield of the solute in the initialethanolic mother liquors. In an even more preferred embodiment, thecatalysed racemization is performed at a suitable temperature andconcentration in-situ during the resoluton in a suitable solvent, priorto the isolation of the first crop of product; this “dynamic resolution”allows a first crop yield of product to be significantly greater thanthe 50% available by traditional salt resolutions. Dynamic resoultionsare known in the art, but suitable conditions are generally highlysubstrate-dependent.

In still another embodiment of a process for preparing an opticalyenriched compound of formula C, commercially available homochiral(S)-L-2-phenylglycine is converted to(S)-4-phenyl-1,3-oxazolidine-2,5-dione using methods well known in theart, which, may then be combined with commercially availableN-methylbenzylamine. The resulting mixture is then subjected to anaqueous work-up, providing the phenylglycinamide, e.g.(S)-N-benzyl-N-methyl-2-phenylglycinamide with 43% e.e. in 49% yield,which may be purified as its hydrochloride salt as described, ordi(o-toluoyl)-L-tartrate salt.

Biological Assays

The selectivity of the apo B secretion/MTP inhibitors was determined bythe following protocols.

Inhibition of Fat Absorption

Healthy female CF1 mice (Charles River) weighing 18-20 grams uponarrival are employed as test subjects. The mice are housed in groups of10 in standard caging, and are allowed to acclimate for one week priorto testing. Mice are fasted overnight in a separate procedure room priorto testing. Each treatment group typically consists of 5 mice.

The test compound is preferably provided as a powder in a glass vial.The dosing solution (0.10 ml/25 g body weight) administered by oralgavage consists of an emulsion of Miglyol 812 (20%), Cremaphor (5%),Water (75%). An appropriate volume of Miglyol is first added to the testcompound, and the vial vortexed for approximately 1 minute. Next, theappropriate volume of Cremaphor is added, and the vial again vortexed aspreviously. The appropriate volume of water is then added, and theemulsion formed by vortexing and briefly sonicating.

Hamster liquid diet (Bioserve F0739) (dose volume 0.5 ml/25 g bodyweight) is prepared by adding (for every 10 mL needed) 2.5 grams liquiddiet powder, 10 mL water and 5 microcuries glycerol-3H-trioleate(Amersham TRA191) to a laboratory blender. The mixture is then blendedat high speed for approximately 1 minute. The liquid diet is stored at4° C. until use.

Sample tubes are weighed (Falcon 15 ml polypropylene conical). Threemilliliters of 2.5N KOH is then added to each tube.

Following overnight fasting, each mouse is dosed (see above volumes)with test compound followed immediately by liquid diet. Positive (aknown potent MTP inhibitor) and negative control groups (vehicle) areincluded in each assay. One scintillation vial is sham dosed every 30mice in order to determine the activity of the initial bolus.

At two hours post dose the mice are euthanized by carbon dioxideinhalation, the abdominal cavity opened, and the small intestinesremoved and placed in the KOH conical tube. Each tube is then weighed.

Tubes containing intestines are then placed in a 75° C. water bath for1.5-2 hours. Following saponification, the tubes are vortexed and 200 μLsaponate placed in a 20 mL liquid scintillation vial. Samples aredecolorized (for 30 minutes) by adding 200 μL of 30% (w/w) hydrogenperoxide. Each sample is neutralized by the addition of 200 μL of 3NHCL. Ten milliliters of Ready Safe® (Beckman) liquid scintillation fluidare added and the samples were counted on a Beckman Coulter LS 6500scintillation system.

The calculations are carried out as follows:

-   -   weight of saponate=weight of tube (KOH+intestine)−weight of        empty tube    -   saponate fraction=0.22/saponate weight (density of the        saponate=1.1 g/mL; therefore the weight of the aliquot is equal        to 0.22 g)    -   total DPM for the entire intestine=DPM of sample/saponate        fraction    -   The initial bolus DPM is calculated by averaging the counts from        the sham dosed scintillation vials.    -   The fraction of bolus recovered from the intestine (percent        recovery)=total DPM/bolus count.    -   Percent recovery from each test group=average of percent        recovery from each mouse.        Interpretation of Results:

To compare efficacy of test compounds, an ED₂₅ for intestinal fatabsorption is calculated. The (average) percent triglyceride recovery(percent unabsorbed and remaining in the intestine) of the vehiclecontrol group is adjusted to equal 0%, and the (average) percentrecovery of the compound control group is adjusted to equal 100%. Thesame calculations are applied to the percent recovery values obtainedfor test compounds and an adjusted percent recovery is obtained (%recovery of the test sample−% recovery of vehicle control group/(%recovery of positive control group−% recovery of vehicle controlgroup)). An ED₂₅ is then calculated by plotting a graph of compoundconcentration vs. adjusted percent recovery.

Serum Triglyceride Lowering

Healthy female CF1 mice (Charles River) weighing 18-20 grams uponarrival are employed as test subjects. The mice are housed in groups of10 in standard caging, and were allowed to acclimate for one week priorto testing. Mice are fasted overnight in a separate procedure room priorto testing. Each treatment group typically consists of 10 mice.

The test compound is preferably provided as a powder in a glass vial.The dosing solution (0.250 ml/25 g body weight) administered by oralgavage consists of an emulsion of Miglyol 812 (40%), Cremaphor (10%),Water (50%). An appropriate volume of Miglyol is first added to the testcompound, and the vial vortexed for approximately 1 minute. Next, theappropriate volume of Cremaphor is added, and the vial again vortexed aspreviously. The appropriate volume of water is then added and theemulsion formed by vortexing and briefly sonicating.

Following overnight fasting, each mouse is dosed (see above volumes)with test compound. At 1 hour post dose the mice are euthanized bycarbon dioxide inhalation and blood collected for triglyceridequantitation.

Serum triglyceride values are quantitated using a calorimetric endpointassay (Wako Triglyceride E kit # 4324021) on a Spectra Max 250 platereader with Softmax Pro software. All samples are run in duplicate.

For comparison of triglyceride values, the percent change from controlis calculated. The average triglyceride value of the test compound groupis divided by the average triglyceride value of the vehicle group,multiplied by 100 and then subtracted from 100%. The ED₂₅ value is thencalculated by plotting a graph of compound concentration versus percentchange from control.

The relative values of the ED₂₅ for triglyceride lowering and the ED₂₅for inhibition of intestinal fat absorption are used as a means tocompare selectivity of the test compounds.

Where HPLC is referred to in the preparations and examples below, thegeneral conditions used, unless otherwise indicated, are as follows: thecolumn used was a Phenomenex Luna™ C-8 column (3.0×250 mm), and thecolumn was eluted using a gradient of 90% A 10% B to 100% B over 45minutes, where solvent A was 0.1% formic acid in water and solvent B wasacetonitrile. The column was run on a Agilent 1100 MSD system.

EXAMPLES Example 1(S)-1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide

(a) 1-Ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester.

5-Nitro-1H-indole-2-carboxylic acid ethyl ester (5 g, 21.3 mol) wasdissolved in DMF (50 mL). The reaction mixture was cooled to 0° C.Sodium hydride (1.02, 25.5 mmol, 60% in mineral oil) was added to theabove solution in portions over 10 minutes. The mixture was stirred atroom temperature for 30 minutes. Ethyl iodide (6.5 g, 42 mmol) was addedto the above solution and the reaction mixture was stirred overnight.Ethanol (30 mL) was added to the reaction mixture and the mixture waspoured into cold water (800 mL). The crude product was collected byfiltration and used directly in next step without further purification(5 g).

(b) 5-Amino-1-ethyl-1H-indole-2-carboxylic acid ethyl ester.

The 1-ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (5 g, 19.1mmol) of step (a) was dissolved in EtOH/n-PrOH (100 mL, 1/1). Palladiumhydroxide (1.14 g) and ammonium formate (3.92 g, 62.2 mmol) were addedto the above solution. The mixture was heated to reflux for 2 hours. Thereaction mixture was cooled to room temperature and the catalyst wasfiltered off through Celite. The solvent was removed under reducedpressure. The crude product was dissolved in dichloromethane (300 mL)and washed with NaHCO₃ (150 ml×2). The organic layer was collected,dried (Na₂SO₄) and evaporated. The crude product was purified bychromatography to furnish the desired product (4 g, 90%).

(c)1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid ethyl ester.

4′-Trifluoromethyl-biphenyl-2-carboxylic acid (5.04 g, 18.95 mmol) and1-ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (4.00 g, 17.23mmol) were dissolved in DCM (100 mL). DIEA (8 g, 61.8 mmol) was added tothe above mixture and the mixture was stirred at room temperature for 5minutes. PyBroP (9.63 g, 20.67 mmol) was added to the above solution inone portion. The reaction mixture was stirred for another 3 hours. Theprecipitate was filtered off and washed with cold DCM to provide thetitle compound (4.5 g, 54.4%).

(d)1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid.

1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid ethyl ester (4.5 g, 9.37 mmol) was added to MeOH/H₂O (110 mL,10/1). Lithium hydroxide monohydrate (1.5 g, 35.7 mmol) was added to theabove mixture. The mixture which resulted was heated to refluxovernight. The solvent was removed under reduced pressure and theresidue was dissolved in H₂O (500 mL). The solution was acidified with6N HCl to pH 2. The solid was collected by filtration and dried undervacuum (4.0 g, 94.5%).

(e) (S)-(Benzylcarbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester.

(S)-tert-Butoxycarbonylamino-phenyl-acetic acid (1.00 g, 4 mmol) wasdissolved in DCM (15 mL). Benzylamine (0.428 g, 4 mmol) and DIEA (0.65g, 5 mmol) were added to the above mixture. The mixture which resultedwas stirred at room temperature for a few minutes. PyBroP (2.10 g, 4.5mmol) was added to the above solution in one portion and the reactionmixture was stirred overnight. The reaction mixture was diluted with DCM(150 mL) and washed with NaHCO₃ (50 mL×2, sat.). The organic layer wascollected and dried (Na₂SO₄) and the solvent was removed under reducedpressure. The crude product was purified by chromatography to providethe desired product (0.85 g, 62%).

(f) (S)-2-Amino-N-benzyl-2-phenyl-acetamide hydrochloride.

(S)-(Benzylcarbamoyl-phenyl-methyl)-carbamic acid tert-butyl ester (0.85g, 2.50 mmol) was dissolved in HCl/dioxane (10 mL, 4.0M). The mixturewas stirred at room temperature overnight. The volatiles were removedunder reduced pressure to provide the desired product in quantitativeyield.

(g)(S)-1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-(benzylamino)-2-oxo-1-phenylethyl]amide

1-Ethyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid (0.05 g, 0.11 mmol) and (S)-2-Amino-N-benzyl-2-phenyl-acetamidehydrochloride (0.031 g, 0.11 mmol) were combined in DCM (3 mL) and DIEA(1.1 mL) was added to the above mixture. PyBroP (0.077 g, 0.17 mmol) wasadded to the above mixture in one portion. The mixture which wasresulted was stirred overnight. The crude mixture was then purified byHPLC to furnish the desired product (52.7 mg). HPLC retention time16.892 min.; Mol. Wt. (calc) 674.7; MS (found) 675.2.

Examples 2-24 were prepared similarly to the above example. In each ofExamples 2-24, the A group comprised(4′-trifluoromethyl)-biphenyl-2-carbonyl linked to a 5-amino group ofB1.

In Examples 6, 11 and 16, R⁶ and R⁷ together with the nitrogen atom towhich they are attached comprise the listed heterocyclyl group. Thebenzylation of the indole nitrogen in Example 14 was performed similarlyto Example 1, step (a). All of the required amines HNR⁶R⁷ arecommercially available or readily prepared using methods well-known inthe art.

TABLE 2

mol. wt. MS HPLC Example R⁴ R⁶ R⁷ (calc) (found) (min) 2 Methyl H4-Methoxy-benzyl 690.729 691.2 15.98 3 Propyl Methyl Benzyl 702.783703.2 20.797 4 Propyl H Butyl 654.739 655.2 18.478 5 propyl Methyl Butyl668.766 669.2 21.237 6 Propyl Morpholin-4-yl 668.722 669.2 16.102 7 HEthyl Ethyl 612.658 613.2 15.158 8 Ethyl H Isopropylmethyl 640.712 641.217.318 9 Ethyl Methyl Benzyl 688.756 689.2 19.712 10 Ethyl Methyl Propyl640.712 641.2 18.505 11 Ethyl Pyrrolidin-1-yl 638.696 639.2 16.558 12 HH Propyl 598.63 599.2 13.357 13 H H Cyclopropylmethyl 610.642 611.213.741 14 Benzyl H Isopropylmethyl 702.783 703.2 19.25 15 Propyl HBenzyl 688.756 689.2 24.897 16 H Pyrrolidin-1-yl 610.642 611.2 13.337 17H Methyl Pyridin-3-ylmethyl 661.69 662.2 5.671 18 Methyl MethylPyridin-3-ylmethyl 675.717 676.2 7.099 19 Benzyl MethylPyridin-3-ylmethyl 751.816 752.2 16.229 20 Ethyl H 3-methyl-benzyl688.756 689.2 18.511 21 Benzyl H 3-methyl-benzyl 750.828 751.2 20.242 22Benzyl H 2-phenyl-prop-2-yl 764.855 765.2 21.217 23 Benzyl H4-methyl-benzyl 750.828 751.2 20.209 24 Methyl H 4-fluoro-benzyl 678.693679.2 16.585

Example 251-Methyl-5-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid (2-methylamino-2-oxo-1-phenylethyl)amide

(a) 6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl esterwas prepared according to methods well-known in the art (see, e.g.,WO00/05201).

(b) 6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid.

6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester (3.5g, 11.90 mmol) was dissolved in MeOH/H₂O (60 mL, 5/1). Lithium hydroxidemonohydrate (0.75 g, 17.8 mmol) was added to the above solution. Themixture which resulted was heated to reflux overnight. The solvent wasremoved under reduced pressure and the residue was dissolved in H₂O (150mL). The solution was acidified with HCl (6N) to a pH of about 2. Thesolid was collected by filtration and dried under vacuum (2.5 g, 75%).MS: 280.2. H¹NMR (DMSO-d₆): δ 2.01 (s, 3H), 7.40 (m, 3H), 7.49 (d, 1H,J=7.3 Hz), 7.65 (d, 1H, J=7.3 Hz), 7.75 (d, 2H, 8.3 Hz).

(c)1-Methyl-5-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid ethyl ester was prepared similarly to Example 1, step (c).

(d)1-Methyl-5-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid was prepared similarly to Example 1, step (d).

(e)1-Methyl-5-[(6-methyl-4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid (2-methylamino-2-oxo-1-phenylethyl)amide was prepared similarly toExample 1, step (g).

The compounds in Table 3 were prepared similarly to Example 25. InExamples 28 and 29, R⁶ and R⁷ together with the nitrogen atom to whichthey are attached comprise the listed heterocyclyl group.

TABLE 3

Ex- am- Mol. Wt. HPLC ple R⁴ R⁶ R⁷ (calc) MS (min) 26 Methyl MethylBenzyl 688.756 689.9 19.563 27 Methyl H Cyclopropyl- 638.696 639.816.245 methyl 28 Methyl Morpholin-1-yl 654.695 655.7 14.74 29 MethylPyrrolidin-1-yl 638.696 639.4 16.269 30 Methyl H Propyl 626.685 627.815.959 31 Methyl Methyl Pyridin-3- 689.744 690.7 7.821 ylmethyl 32Methyl H 4-methoxy- 704.756 705.9 16.961 benzyl 33 Methyl H 4-carboxylic732.766 733.9 16.564 acid methyl ester 34 Methyl H Propen-3-yl 624.6689625.8 15.356 35 Methyl H Methyl 598.63 599.3 13.269

Example 361-Methyl-5-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide

(a) 2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester wasprepared according to the literature (WO00/05201).

(b) 2-(4-Trifluoromethyl-phenyl)-nicotinic acid was prepared similarlyto 6-Methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid as describedin Example 25.

(c)1-Methyl-5-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-1H-indole-2-carboxylicacid ethyl ester was prepared similarly to Example 1, step (c).

(d)1-Methyl-5-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-1H-indole-2-carboxylicacid was prepared similarly to Example 1, step (d).

(e)1-Methyl-5-{[2-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}amide was preparedsimilarly to Example 1, step (g).

The compounds in Table 4 were prepared similarly to Example 36. InExamples 40 and 41, R⁶ and R⁷ together with the nitrogen atom to whichthey are attached comprise the listed heterocyclyl group.

TABLE 4

Ex- Mol. am- wt. HPLC ple R⁴ R⁶ R⁷ (calc) MS (min) 37 Methyl Ethyl Ethyl38 Methyl H Cyclopropylmethyl 625.65 626.8 11.50 39 Methyl H Benzyl661.69 662.8 12.95 40 Methyl Morpholin-4-yl 641.65 642.5 9.72 41 MethylPyrrolidin-1-yl 625.65 626.5 11.44 42 Methyl Methyl Pyridin-3-yl 676.70677.5 3.72 43 Methyl H 4-carboxylic acid 719.73 720.8 12.10 methyl ester

Example 44

Where HPLC is referred to in steps (c), (d), (e), and (f) of thisexample below, unless otherwise stated, the conditions used are asfollows: the column used was a Jones Genesis C-18 300 4μ column (150 mm,part No. FM15960E), and the column was eluted using a gradient of 95% A5% B to 10% A 90% B over 12 minutes, where solvent A was 0.1%trifluorocaetic acid in water and solvent B was 0.1% trifluorocaeticacid in acetonitrile, with a flow rate of 1.5 ml/min. The column was runon a Hewlett Packard 1100 system.

(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide

(a) Ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate was prepared bymethylation of ethyl 5-nitro-1H-indole-2-carboxylate using methods wellknown in the art (see, e.g., E. F. V. Scriven et al., J.C.S., P.T.1,(1979) p.53-59). For example, methylation may be achieved using anycompatible combination of electrophilic methylating agent, i.e., H₃C-LG,where LG is a leaving group, and a base, e.g., using dimethylsulfate,methyl iodide (Example 45, step (a)) or methyl tosylate, with bases suchas sodium hydride, potassium t-butoxide or potassium carbonate.Preferably, methyl tosylate and potassium carbonate are used as follows:

To a refluxing mixture of commercially available ethyl5-nitro-1H-indole-2-carboxylate (420 g) and potassium carbonate (272.6g) in acetonitrile (3360 mL) was added a solution of methylp-toluenesulfonate (367.3 g) in acetonitrile (630 mL), and the resultingmixture refluxed for 18 hours. The mixture was then cooled to 20° C.over 3 hours and water (4200 mL) added over a 3 hour period. The productwas granulated, filtered, washed with a 50/50 mixture of demineralizedwater and acetonitrile (630 mL), demineralized water (420 mL) and thenwith ethanol (420 mL), and dried, yielding the product ethyl1-methyl-5-nitro-1H-indole-2-carboxylate (436.1 g, 96%).

(b) Ethyl 5-amino-1-methyl-1H-indole-2-carboxylate.

Alternative A. To a mixture of ethyl1-methyl-5-nitro-1H-indole-2-carboxylate (420 g), from step (a) orcommercial sources, and 10% palladium on carbon catalyst (50% wet) (42g) in ethanol (4200 mL) was added a solution of ammonium formate (541.5g) in demineralized water (840 mL) at between 25-35° C. over 3 hours.The mixture was stirred for 18 hours at 20° C., and then filtered,washing the solids with ethanol (2100 mL). The combined filtrate andwashings were concentrated to 840 mL under vacuum at about 20° C. Theresulting slurry was granulated at 5° C., filtered, washed with chilledethanol (420 mL), and dried to give product ethyl5-amino-1-methyl-1H-indole-2-carboxylate (316.5 g, 86%).

Preferred alternative B. A mixture of ethyl1-methyl-5-nitro-1H-indole-2-carboxylate (150.0 g), from step (a) orcommercial sources, and 10% palladium on carbon catalyst (50% wet) (15.0g) in ethyl acetate (1800 mL) was hydrogenated at 3 bar at 30° C. for 8hours. The mixture was then filtered and the solids washed with ethylacetate (300 mL). The combined filtrate and washings were partiallyazeotropically dried at reflux and then concentrated to 800 mL to give asolution of product ethyl 5-amino-1-methyl-1H-indole-2-carboxylate inethyl acetate.

The acid salts of ethyl 5-amino-1-methyl-1H-indole-2-carboxylate arealso readily available via methods well-known in the art. For example,the hydrochloride salt is readily prepared by treating an ethylacetatesolution of the amine with hydrochloric acid in propan-2-ol.

(c) Ethyl1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate

Alternative A. 4′-(Trifluoromethyl)[1,1′-biphenyl]-2-carboxylic acid(133 g), commercially available, thionyl chloride (89 g) and a catalyticamount of N,N-dimethylbenzamide (2.3 g) were combined in toluene (665mL) at 55-60° C. over 2 hours, and the mixture heated at 80° C. for 1hour. The excess reagent was removed by atmospheric co-distillation withtoluene (600 ml distillate removed), providing a solution of4′-(trifluoromethyl)[1,1′-biphenyl]-2-carbonyl chloride, which wascombined with ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (109 g)from the previous step, ethyl acetate (4660 ml) andN,N-diisopropylethylamine (131 mL) at 18-29° C. The resulting slurry wascooled, filtered and the crude product solids were washed withpropan-2-ol (330 mL). The crude product was twice reslurried in a 70/30mixture of demineralized water and propan-2-ol (2×1500 mL), and thesolids were filtered, washed with propan-2-ol (400 mL) and dried,yielding the title compound, ethyl1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate(167 g, 71.8%).

Preferred alternative B. A solution of commercially available4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxylic acid (150.0 g) intoluene (975 ml) and acetonitrile (1275 mL) was added to a solution ofthionyl chloride (100.4 g) and N-methylpyrrolidone (3.7 g) in toluene(750 mL) at reflux. The resulting mixture was heated at reflux for 18hrs, then the acetonitrile and excess thionyl chloride were distilledoff by reducing the volume to 900 mL. Additional toluene (2250 mL) wasthen added before re-concentrating to provide a solution of theintermediate acid chloride(4′-(trifluoromethyl)(1,1′-biphenyl]-2-carbonyl chloride) (900 mL). Thissolution was then diluted with ethyl acetate (2620 mL) andN,N-diisopropylethylamine (109.5 g) was added. An ethyl acetate solutionof ethyl 5-amino-1-methyl-1H-indole-2-carboxylate (1.07 moleequivalents), from step (b), (solution volume 800 mL) was then added intwo portions at 20-25° C., seeding with product (ethyl1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate)between portions. The crude product was granulated overnight thenisolated by filtration and washed with propan-2-ol (450 mL). The crudeproduct was twice reslurried in a 75/25 mixture of demineralized waterand propan-2-ol (2×180 mL), and the solids were filtered, washed withpropan-2-ol (450 mL) and dried, yielding product (ethyl1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate)(196 g, 74.5%). Mol wt (calc) 466.46, MS: 467.1 (MH⁺). ¹H NMR (DMSO-d₆):δ 1.31 (t, 3H, J=7.2 Hz), 3.97 (s, 3H), 4.30 (q, 2H, J=7.2 Hz), 7.12 (s,1H), 7.34 (d, 1H), 7.46-7.74 (complex, 9H), 7.93 (s, 1H), 10.22 (s,1H).; HPLC retention time 11.10 minutes.

(d) Alternative A.1-Methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid sodium salt hydrate.

Ethyl1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate(46.7 g) from the previous step and aqueous sodium hydroxide (8.0 g in140 ml) were combined in refluxing ethanol (280 mL) for 1 hour. Thesolution was cooled, granulating overnight and the resulting slurry wasfiltered. The product solids were washed with an ethanol-water mixtureand dried, yielding the title compound,1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid sodium salt hydrate (36.3 g, 79% as-is). Anhydrous Mol wt of parentacid (calc) 438.41, MS: 439.2 (MH⁺), 437.0 (M⁻). ¹H NMR (DMSO-d₆): δ4.00 (s, 3H), 6.55 (s, 1H), 7.12-7.75 (complex, 11H), 10.04 (s, 1H).;HPLC retention time 9.30 minutes.

Alternative B.1-Methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid hemihydrate.

1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid sodium salt hydrate (0.62 g), from the previous alternative, andaqueous hydrochloric acid (2 molar) were combined in refluxing ethanol(13 mL) and water (1.3 mL). The mixture was cooled, granulatingovernight, chilled in ice and the resulting slurry was filtered. Theproduct solids were dried, yielding the title compound,1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid hydrate (0.5 g, 83%, containing 2% water by weight). Anhydrous Molwt (calc) 438.41, MS: 439.35 (MH⁺), 437.20 (M⁻). ¹H NMR (DMSO-d₆): δ3.97 (s, 3H), 7.13 (s, 1H), 7.30-7.75 (complex, 10H), 7.92 (s, 1H),10.21 (s, 1H).; HPLC retention time 9.29 minutes.

Preferred Alternative C.1-Methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]1H-indole-2-carboxylicacid potassium salt 2.6 hydrate.

A solution of potassium hydroxide (54.1 g) in water (600 mL) was addedover 15 minutes to a suspension of ethyl1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate(300 g), from the previous step, in propan-2-ol (4500 mL) at 60° C. andthe resulting mixture was heated to reflux for an hour. The solution wasseeded with product(1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid potassium salt) and the mixture granulated at 60-70° C. for twohours. The mixture was slowly cooled to 0-5° C. and the productpotassium salt collected by filtration, washing with a chilled 90/10mixture of propan-2-ol and demineralized water (510 mL total volume).The product solids were dried, yielding1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid potassium salt 2.6 hydrate (287.4 g, 85% correcting for watercontent of 9.1% by weight). Anhydrous Mol wt of parent acid (calc)438.41, MS: 439.3 (MH⁺), 437.3 (M⁻). ¹H NMR (DMSO-d₆): δ 3.99 (s, 3H),6.53 (s, 1H), 7.12-7.76 (complex, 11H), 10.05 (broad), HPLC retentiontime 9.30 minutes. The preferred solid form of the product ischaracterized by the pXRD (powder X-ray diffraction) pattern shown inFIG. 7.

(e) (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride monohydrate

(S)-N-tert-butoxycarbonyl-2-phenylglycine (250 g) and1-hydroxybenzotriazole hydrate (136.2 g) andN,N′-dicyclohexylcarbodimide (205.1 g) were combined in dichloromethane(3000 mL) at 0-5° C. and the mixture stirred for 15 minutes. A solutionof N-methylbenzylamine (128.1 mL) in dichloromethane (835 mL) was addedslowly, maintaining 0-5° C. The resulting slurry was allowed to warm toroom temperature overnight before being filtered, washing the by-productsolids with dichloromethane (500 mL). The combined filtrate was twicewashed with saturated aqueous sodium hydrogen carbonate (2×1500 mL),twice washed with 50% saturated aqueous sodium hydrogen carbonatesolution (2×1500 mL), once washed with 2.5% aqueous citric acid solution(1500 mL) and once washed with demineralized water (1500 mL), providinga dichloromethane solution of tert-butyl(S)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate. Analysis bychiral HPLC showed that 2% of the wrong enantiomer (tert-butyl(R)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate) to be presentat this stage.

The solvent was replaced with propan-2-ol (2400 mL) via distillation at20-25° C. and the solution cooled to and maintained at 0-5° C. duringthe addition of concentrated hydrochloric acid (1000 mL). The resultingsolution was allowed to warm to room temperature overnight before theexcess reagent byproducts and water were removed by co-distillation withadditional propan-2-ol (8000 mL), providing a concentrated solution ofproduct at 50-60° C. The product was precipitated by the addition oftert-butyl methyl ether (1875 mL) maintaining 50-60° C. and seeding. Theresulting slurry was cooled to 20° C., and the solids were filtered,washed with tert-butyl methyl ether (500 mL) and dried, yielding product(S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride monohydrate(190.8 g, 62% corrected for water content of 6.35% by weight). Analysisby chiral CE showed that 0.2% of the wrong enantiomer((R)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride monohydrate) tobe present at this stage. Anhydrous Mol wt of parent amine (calc)254.33, MS: 255.4 (MH⁺). ¹H NMR (DMSO-d₆): major/minor rotomers δ 3.298(s, 3H), 4.46/4.55 (m=2×dd, 2H), 5.55/5.57 (2×s, 1H), 6.93-7.57(complex, 10H), 8.70 (s broad, 3H), HPLC retention time 5.87 minutes.

The preferred solid form of the product is characterized by the XRD(X-ray diffraction) data shown in FIG. 6.

(f)(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide

1-Methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid sodium salt (16.0 g), from step (d) alternative A, methanesulfonicacid (2.24 mL), 1-hydroxybenzotriazole hydrate (5.32 g) andN-[3-(dimethylamino)propyl-N′-ethylcarbodimide hydrochloride (8.66 g)were combined in dichloromethane (384 mL) at 0-5° C. and the mixturestirred for 1 hour. Triethylamine (4.78 ml mL) was added followed by aslurry of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride (11.1g), from step (e), in dichloromethane (48 mL) was added slowly,maintaining 0-5° C. The resulting slurry was allowed to warm to roomtemperature overnight. Further triethylamine (2.4 mL) was added at 0° C.After approximately 2 hours, the mixture was twice washed with saturatedaqueous sodium hydrogen carbonate (2×200 mL), once washed with 0.5Maqueous hydrochloric acid solution (200 mL) and once washed withdemineralized water (200 mL) adjusting to pH=6 with aqueous sodiumhydrogen carbonate solution, providing a dichloromethane solution of(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide.

Using the dichloromethane solution of the title compound, the solventwas replaced with propan-2-ol (32 mL) via distillation, the warmsolution was diluted with tert-butyl methyl ether (170 mL), cooled andseeded. The product was collected in three initial crops (77%). Thesewere combined with their mother liquors in dichloromethane (75 mL) toprovide a solution. The solvent was again replaced with propan-2-ol (32mL) via distillation, the warm solution was diluted with tert-butylmethyl ether (160 mL), cooled to room temperature, concentrated to halfvolume, and granulated overnight. The resulting slurry was filtered andthe cake washed with a 1:1 mixture of propan-2-ol and tert-butyl methylether and dried in vacuum, yielding product(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamidein Form A (16.3 g, 69.5%). MS: 675.1 (MH⁺). ¹H NMR (DMSO-d₆):major/minor rotomers δ 2.89/2.78 (s, 3H), 3.94/3.90 (s, 3H), 4.57(m=2×dd, 2H), 6.07/6.13 (d, 1H, J=7.4/7.4 Hz), 7.11-7.76 (complex, 21H),7.86 (s, 1H), 8.79/8.84 (d, 1H, J=7.4/7.7 Hz), 10.20 (s, 1H). Mol wt(calc) 674.73; MS 675.2. HPLC retention time 17.948 minutes using thestandard conditions cited before Example 1.

The preferred solid form of the product, Form A, is characterized by thepXRD (powder X-ray diffraction) pattern shown in FIG. 1 and DSC(differential scanning calorimetry) trace shown in FIG. 2.

Alternatively and preferably, the title compound is prepared as follows:A solution of methanesulfonic acid (34.0 g) in dichloromethane (85 mL)was added to a mixture of1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylicacid potassium salt hydrate (170 g), from step (d) alternative C, and1-hydroxybenzotriazole hydrate (54.6 g) in dichloromethane (3400 mL) at0° C. N-[3-(dimethylamino)propyl-N′-ethylcarbodimide hydrochloride (88.4g) in dichloromethane (680 mL) was then added over 30 minutes and theresulting mixture stirred at 0° C. for 1 hour. Triethylamine (53.9 g) indichloromethane (170 mL) was then added over 10 minutes followed by asolution of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloridehydrate (120.6 g), from step (e), in dichloromethane (680 mL) and theresulting mixture stirred at 0° C. for 30 minutes before allowing towarm to 20° C. for 16 hours. The mixture was twice washed with saturatedaqueous sodium hydrogen carbonate (2×2040 mL), once washed with 0.25Maqueous hydrochloric acid solution (2040 mL) and once washed withdemineralized water (2040 mL). The resulting product solution wasconcentrated to 595 mL under reduced pressure and the concentratecombined with an acidic ion-exchange resin (240 g) in propan-2-ol (595mL). The mixture was stirred for 2 hours before filtering, washing thesolids with a 50/50 mixture of propan-2-ol and dichloromethane (170 mL)and concentrating to a volume of 595 mL. The solution was diluted withpropan-2-ol (510 mL) and then re-concentrated to a volume of 595 mLbefore diluting with tert-butyl methyl ether (1700 mL). The resultingsolution was cooled to 20° C. and seeded and the mixture stirred for 18hours before concentrating to a volume of 920 mL under reduced pressure.After further granulation at 20° C. for an additional 48 hours theslurry was filtered and washed with cold propan-2-ol (340 mL). Theproduct solids were dried, yielding the product(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamidein Form A (192 g, 80%). HPLC retention time 11.50 minutes using theconditions specific to this example (noted above).

Alternative solid Form B of the title compound is prepared as follows:The title compound (150.7 g), prepared by any of the methods described,was dissolved in acetonitrile (350 mL) and filtered. Further titlecompound (30.8 g) was then added as a seed and the resulting mixturediluted with diisopropyl ether (3300 mL) and granulated at 20-25° C. for48 hours. The solids were filtered, washed with diisopropyl ether anddried to give the product in Form B (163.5 g, 90%). Form B, ischaracterized by the pXRD (powder X-ray diffraction) pattern shown inFIG. 3.

Alternative solid Form G of the title compound is prepared as follows:The title compound (13.5 g), prepared by any of the methods described,was dissolved in ethanol (100 mL) at elevated temperature and theresulting solution allowed to cool and granulate at 20-25° C. for 48hours. Further ethanol (150 mL) was then added and the resulting mixturegranulated at 20-25° C. for a further 48 hours. A portion of thismixture was filtered and the solids were washed with ethanol beforeseparating into two portions. One portion of solid was dried at ambienttemperature and pressure to give the product in Form G (1.1 g). Form G,is characterized by the pXRD (powder X-ray diffraction) pattern shown inFIG. 4.

Alternative solid Form F of the title compound is prepared as follows:The title compound (13.5 g), prepared by any of the methods described,was dissolved in ethanol (100 mL) at elevated temperature and theresulting solution allowed to cool and granulate at 20-25° C. for 48hours. Further ethanol (150 mL) was then added and the resulting mixturegranulated at 20-25° C. for a further 48 hours. A portion of thismixture was filtered and the solids were washed with ethanol beforeseparating into two portions. One portion of solid was dried undervacuum at 50° C. to give the product in Form F (1.29). Form F, ischaracterized by the pXRD (powder X-ray diffraction) pattern shown inFIG. 5.

Alternative solid Form F of the title compound may also be prepared asfollows: The title compound in Form G (1.214 g), prepared by any of themethods described, was dried under vacuum at 50° C. to give the productin Form F (1.195 g). Form F, is characterized by the pXRD (powder X-raydiffraction) pattern shown in FIG. 5.

Example 45

Compounds of formula 1 where R³ is halogen, preferably chloro, wereprepared in the following manner:

(a) 1N-methyl-5-nitroindole-2-carboxylic acid ethyl ester.

To a solution of 5-nitroindole-2-carboxylic acid ethyl ester (30.45 g,130 mmol) in DMF (200 mL) was added 60% NaH (6.4 g, 160 mmol) in severalportions, and the mixture was stirred under nitrogen at room temperaturefor 30 minutes. To this was then slowly added methyl iodide (15.56 mL,250 mmol), and the stirring was continued for 2 hours. The reactionmixture was quenched with 0.5 N HCl solution (400 mL) and extracted with2:1 EtOAc/benzene solution (600 mL. The organic layer was washed withwater (500 mL), brine (500 mL), dried over MgSO₄, and then concentratedin vacuo to give 26.7 g of the title compound.

(b) 3-Chloro-1N-methyl-5-nitroindole-2-carboxylic acid ethyl ester.

The product of step (a) (24.8 g, 100 mmol) was dissolved in THF (500mL), followed by the addition of N-chlorosuccinimide (20 g, 150 mmol),and the reaction mixture was stirred at room temperature under nitrogenfor 60 hours. The reaction solution was concentrated in vacuo, and theresidue was taken into EtOAc (750 mL). The organic layer was washed with0.5 N NaOH solution (4×750 mL), brine (750 mL), dried (MgSO₄), andconcentrated in vacuo to afford the crude product which was purified byrecrystallization from ethanol to give 13 g of the title compound

(c) 3-Chloro-1N-methyl-5-amino-indole-2-carboxylic acid ethyl ester.

To a refluxing mixture of hydrazine hydrate (10.8 ml, 222 mmol) andRaney Ni (6 g) in MeOH (200 mL) was slowly added the product of step (b)(12.6 g), and the refluxing was continued for 6 hours. After cooling toroom temperature, the Raney Ni was removed by filtration through Celite,and the solvent was removed in vacuo to give the crude product. Theresidue was dissolved in toluene (100 mL), and concentrated in vacuo.The residue was again dissolved in toluene (100 mL), and concentrated invacuo, the residue was suspended in diethyl ether, and the product wascollected by filtration to afford 11.3 g of the title compound.

(d)3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid ethyl ester

4′-Trifluoromethyl-2-biphenylcarboxylic acid was converted to thecorresponding acid chloride by treatment with oxalyl chloride inmethylene chloride in the presence of catalytic amount of DMF. To asolution of the acid chloride (10.8 g, 38 mmol) and pyridine (3.27 mL,40 mmol) in methylene chloride (200 mL) was added the product of step(c) (10.1 g, 40 mmol), and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction solution was diluted to 600 mL withCH₂Cl₂, washed with 0.1 N HCl solution (2×500 mL) and with brine (500mL), and then dried (MgSO₄). The solvent was evaporated in vacuo to givethe crude product which was purified by recrystallization fromEtOAc/isooctane to afford 13.8 g of the title compound.

(e)3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid

The product of step (d) may be hydrolyzed as follows: the compound (5.51g) was dissolved in THF (120 mL) and methanol (40 mL). Under stirringconditions was added LiOH (1.32 g) in water (40 mL). The reactionmixture was stirred at room temperature overnight. To the reactionmixture was then added 1 N HCl solution (60 mL), and the aqueous layerwas extracted with EtOAc (250 mL). The organic layer was washed withbrine (200 mL), and dried (MgSO₄). The solvent was evaporated in vacuoto give the crude product which was purified by recrystallization from1:1 EtOAc/ether to afford 4.4 g of the title compound.

(f)3-Chloro-1-methyl-5-[methyl-(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid

As an alternative to step (e), the product of step (d), in which R⁹ ishydrogen, optionally may be alkylated by processes well known in theart. For example, to prepare a compound in which R⁹=methyl, the productof step (d) is treated with Me₂SO₄ in the presence of KOH, K₂CO₃ andBu₄NHSO₄ in a suitable solvent such as toluene, with heating to 70° C.with stirring for about 30 minutes. After cooling to room temperature,the reaction mixture is diluted with 1 N HCl and stirred for 10 min.EtOAc (100 mL) is then added, and the organic layer washed with brine,dried (MgSO₄), and solvent removed in vacuo to give the product whereinR⁹ is methyl, with appropriate purification e.g., by recrystallizationfrom 1:2 EtOAc/isooctane.

The resulting indole ester may then be hydrolysed as in step (e), e.g.,as follows: the compound is dissolved in 3:1 THF:methanol, LiOH in wateris added under stirring conditions and the reaction mixture is stirredat room temperature overnight. To the reaction mixture is then added 1 NHCl solution, and the aqueous layer s extracted with EtOAc (about 2volumes). The organic layer is washed with brine, and dried (MgSO₄). Thesolvent is evaporated in vacuo to give the crude product which may bepurified by recrystallization from 1:1 EtOAc/ether to afford an indolecarboxylic acid of formula AB1.

The products of steps (e) and (f), i.e., compounds of formula AB1, maybe amide linked to compounds of formula C by methods which are wellknown in the art, an example of which is described below in step (g)

(g)3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-(isopropylamino)-2-oxo-1-phenylethyl]amide

The product from step (e) (292.5 mg, 0.619 mmol),(S)-N-isopropyl-2-phenylglycinamide hydrochloride salt (182.1 mg, 0.797mmol), PyBroP (415.8 mg, 0.865 mmol) were suspended in anhydrous CH₂Cl₂(6 ml), followed by the addition of DIEA (0.36 ml, 2.07 mmol). Thereaction mixture was stirred at room temperature for 3.5 h. The productwas purified by flash chromatography using 30:70 of hexane:EtOAc toafford 345.5 mg of the title compound.

Examples 46-65 were prepared similarly to Example 45 above, and Examples65b-f were prepared similarly to Example 65a below.

TABLE 5

Mol wt. MS HPLC Example R⁴ R⁵ R⁶ R⁷ R⁹ R¹³ (calc) (found) (min) 46Methyl H Methyl Benzyl H Trifluoromethyl 709.17 709.2 20.185 47 Methyl HH Propyn-3-yl H Trifluoromethyl 643.07 643.2 15.244 48 Methyl H HIsopropyl H Trifluoromethyl 647.10 647.2 16.567 49 Methyl H MethylPyrid-3-yl H Trifluoromethyl 710.16 710.2 8.513 50 Methyl H H Propyl HTrifluoromethyl 647.10 647.2 16.67 51 Methyl H Ethyl Benzyl HTrifluoromethyl 723.20 723.2 21.392 52 Methyl H Methyl 3-chloro- HTrifluoromethyl 743.61 744.2 20.578 benzyl 53 Methyl H Methyl BenzylMethyl Trifiuoromethyl 723.20 723.2 21.202 54 Methyl H H Ethyl MethylTrifluoromethyl 647.10 647.2 15.615 55 Methyl H H Isopropyl MethylTrifluoromethyl 661.1 661.2 17.161 56 Methyl H Methyl Pyrid-3-yl MethylTrifluoromethyl 724.18 724.2 9.154 57 H H Methyl Benzyl HTrifluoromethyl 695.14 695.2 19.131 58 Ethyl H Methyl Benzyl HTrifluoromethyl 723.20 723.2 21.172 59 Ethyl H H 4-methoxy- HTrifluoromethyl 739.20 739.2 18.345 benzyl 60 Methyl Methyl MethylBenzyl H Trifluoromethyl 709.22 709.2 8.966 61 Methoxy- H Methyl BenzylH Trifluoromethyl 739.20 739.2 19.677 methyl 62 Methyl H H Propyl H H579.10 579.2 14.388 63 Methyl H H Isopropyl H H 579.10 579.2 14.327 64Methyl H Methyl Pyrid-2-yl H H 642.16 642.2 11.303 65 Methyl H MethylPyrid-3-yl H H 642.16 642.2 6.322 65b Methyl H Methyl Ethyl HTrifluoromethyl 633.12 633.2 4.318 65c Methyl H H 4-methyl- HTrifluoromethyl 695.19 695.2 11.147 benzyl 65d Methyl H H Propyl HTrifluoromethyl 633.12 633.2 6.923 65e Methyl H Ethyl Ethyl HTrifluoromethyl 647.15 647.2 5.071 65f Methyl H H Methyl HTrifluoromethyl 605.06 605.2 5.433

Example 65a3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-(ethylamino)-2-oxo-1-phenylethyl]amide

(a)3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid (3.41 g, 6.6 mmol), N,O-dimethyl hydroxylamine hydrochloride salt(0.938 g, 9.4 mmol) PyBroP (4.50 g, 9.4 mmol) were suspended in CH₂Cl₂(60 ml), followed by the addition of diisopropylethyl amine, and theresultant reaction mixture was stirred at room temperature for severalhours. The reaction solution was concentrated to ˜25 ml, and thendirectly applied to flash chromatography using 30:70 of EtOAc/hexane togive 2.86 g of the title compound.

(b) 4′-Trifluoromethyl-biphenyl-2-carboxylic acid(3-chloro-2-formyl-1-methyl-1H-indol-5-yl)-amide:

To a solution of the product from step (a) (1.56 g, 3.02 mmol) in THF(25 ml) at −78° C. was added DIBAL in THF (1.0 M, 12 ml), and thereaction mixture was stirred at −78° C. for 6 h. The reaction mixturewas diluted with NaHSO₄ (0.25 M, 86 ml) and EtOAc (115 ml), and theaqueous layer was extracted with EtOAc (2×100 ml). The combined organiclayers were dried (MgSO₄) and concentrated in vacuo to about 30 ml involume. The product was purified by flash chromatography using 1:1EtOAc/hexane to afford 0.706 g of the title compound.

(c)3-Chloro-1-methyl-5-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1H-indole-2-carboxylicacid [2-(ethylamino)-2-oxo-1-phenylethyl]amide.

The product from step (b) (407.5 mg, 0.892 mmol),(S)-N-ethyl-2-phenylglycinamide hydrochloride salt (316.3 mg, 1.47 mmol)and acetic acid (10 drops) were suspended in CH₂Cl₂ (25 mL), and thereaction mixture was stirred at room temperature for 20 min. NaB(OAc)₃H(2.1 eq) was then added, and the reaction mixture was stirred at 50° C.for 5.5 h. Saturated NaHCO₃ (8 mL) and CHCl₃ (12 mL) were then added,and the organic layer was washed with water (6 mL), and thenconcentrated in vacuo. The product was purified by flash chromatographyusing 30:70 of hexane:EtOAc to afford 441.4 mg of the title compound.

Examples 66-85

Using a compound of formula B1C, substituted biphenyl “A” groups wereamide linked to form the compounds shown in Table 6 according to thefollowing method:

A stock solution containing compound B1C (20.4 mg, 0.0478 mmol), EDC(19.6 mg, 0.102 mmol), and DMAP (2.47 mg, 0.020 mmol) in CH₂Cl₂ (0.8 ml)was added to a 1.8 mL reaction vial containing the acid (1.2 eq), andthe resulting mixture was shaken at room temperature overnight. To thereaction mixture was then added 0.5 ml of N,N-dimethylethylenediamineand the reaction mixture was then shaken for 18 h. The product waspurified by silica gel chromatography using CH₂Cl₂/EtOAc. The yieldsranged from about 70% to about 95%.

TABLE 6

Example R¹³ Other R¹³ (if present) Mol. wt. 66 3′-fluoro 5′-fluoro642.712 67 2′-fluoro 4′-fluoro 642.712 68 3′-trifluoromethyl5′-trifluoromethyl 742.728 69 4′-chloro — 641.176 70 3′-methyl — 620.75871 3′-carboxylic acid — 650.741 72 3′-chloro 4′-fluoro 659.166 734′-methoxy — 652.822 74 3′-amino — 621.746 75 3′-methoxy — 636.757 763′-carboxymethyl — 648.768 77 3′carbamoylmethyl — 663.783 78 4′-ethenyl— 632.769 79 2′-methoxy 4′-methoxy 666.7841 80 4′-hydroxymethyl —636.757 81 2′-methoxy 5′-chloro 671.202 82 4′-cyano — 631.741 834-tert-butyl — 662.839 84 3′-methoxy 4′-methoxy 666.7841 85 3′-fluoro4′-fluoro 642.712

Example 86 (S)-5-(2-Butoxy-benzoylamino)-1-methyl-1H-indole-2-carboxylicacid {2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-amide

(a) 5-(2-Acetoxy-benzoylamino)-1-methyl-1H-indole-2-carboxylic acidethyl ester

To a solution of 5-amino-1-methyl-indole-2-carboxylic acid ethyl ester(12.86 g, 58.92 mM) and diisopropylethylamine (20.5 mL, 117.84 mM) inCH₂Cl₂ at 0° C. was added a solution of acetyl salicyloyl chloride inCH₂Cl₂ over 30 minutes. After the addition was complete the cooling bathwas removed and the mixture was allowed to warm to room temperature andstirred at that temperature for 2 hours. The mixture was transferred toa separatory funnel and the solution was washed with 1N HCl (150 mL) andaqueous NaHCO₃. The organic fraction was dried over MgSO₄ and filtered.The solvent was removed under reduced pressure to provide the titlecompound.

(b) 5-(2-Hydroxy-benzoylamino)-1-methyl-1H-indole-2-carboxylic acid.

The product of step (a) (2.0 g, 5.26 mM) was dissolved in THF (30 mL),methanol (10 mL), and water (10 mL). The mixture was treated withlithium hydroxide (882 mg, 21.04 mM) and the mixture was stirred at roomtemperature for 3 hours. The mixture was concentrated to 15 mL and thepH was adjusted to about 3.0 with 1 N HCl. The mixture was extracted 3times with ethyl acetate (25 mL). The ethyl acetate fractions werecombined, dried over MgSO₄, filtered and concentrated to provide thetitle compound.

(c) (S)-5-(2-Hydroxy-benzoylamino)-1-methyl-1H-indole-2-carboxylic acid{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-amide.

The product of step (b) (1.36 g, 4.38 mM), PyBrOP (2.45 g, 5.26 mM), and(S)-N-benzyl-N-methyl-2-phenylglycinamide (1.91 g, 6.57 mM) were placedin a 50 mL round bottom flask. DMF (20 mL) was added and the mixture wascooled to 0° C. and treated with diisopropyl ethylamine (3 mL, 17.52mM). After the addition was complete the cooling bath was removed andthe reaction mixture was stirred at room temperature for 16 h. Themixture was diluted with ethyl acetate (120 mL) and the mixture waswashed with 1 N HCl (20 mL), water (20 mL) and brine (20 mL). The ethylacetate was dried with MgSO₄, filtered and concentrated. The residue waspurified by flash column chromatography on silica gel eluting with 5%diethyl ether in CH₂Cl₂.

(d) (S)-5-(2-Butoxy-benzoylamino)-1-methyl-1H-indole-2-carboxylic acid{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-amide.

To a solution of the product of step (c) (120 mg, 0.22 mM),triphenylphosphine (68 mg, 0.26 mM), and an alcohol (0.29 mM) in THF (2mL) at 0° C. was added DEAD (41 uL, 0.26 mM). The cooling bath wasremoved and the mixture was stirred at room temperature for 16 hours.The mixture was concentrated to approximately 200 uL and applied to aprep TLC plate (silica gel 60 F254, 1.0 mm, 20 cm×20 cm). The plate waseluted with 5% diethyl ether in CH₂Cl₂. The band corresponding toproduct was scraped off the plate. The product was washed from thesilica gel with ethyl acetate. The ethyl acetate was concentrated toprovide the title product. Mol wt. (calc), 602.74; MS, 603; HPLC, 19.7minutes.

Examples 87-98 shown in Table 7 were prepared similarly to Example 86.

TABLE 7

Ex- am- Mol wt ple R¹⁷ (calc) MS HPLC (min) 87 2-propyl 588.71 589 18.088 4-triflouromethylbutyl 656.71 657 18.0 89 2-methylpropyl 602.74 60319.7 90 2-methylbutyl 616.77 617 21.1 91 2-ethylbutyl 630.79 631 22.3 92Allyl 586.7 587 17.1 93 Cyclopentyl 614.75 615 20.0 94 Methylcyclzohexyl642.8 643 22.7 95 Methylcyclopropyl 600.72 601 18.5 96 2-phenoxyethyl666.78 667 18.8 97 2-ethoxyethyl 618.74 619 16.7 98 H 546.63 547 15.3

Example 995-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzofuran-2-carboxylicacid [2-oxo-1-phenyl-2-(propylamino)ethyl]amide

(a) 5-nitrobenzofuran-2-carboxylic acid methyl ester.

5-Nitrobenzofuran-2-carboxylic acid (10 g) was dissolved in methanol(200 mL) and chloroform (100 mL), and the mixture was cooled to 0° C.Under stirring conditions was bubbled HCl gas until the solution wassaturated. The reaction mixture was stirred at room temperatureovernight, and white solid was formed. The precipitate was collected byfiltration to afford 9.5 g of the title compound.

(b) 5-aminobenzofuran-2-carboxylic acid methyl ester.

The product from step (a) (6.9 g) was dissolved in THF (200 mL),followed by the addition of 10% Pd/C (1 g), and the resulting reactionmixture was hydrogenated under 50 psi of hydrogen for 2 hours. Thecatalyst was removed by filtration through celite, and the solvent wasremoved in vacuo to provide 5.9 g of the title compound.

(c)5-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzofuran-2-carboxylicacid methyl ester.

4′-Trifluoromethyl-2-biphenylcarboxylic acid (9.14 g) was dissolved inCH₂Cl₂, followed by the addition of oxalyl chloride (4.49 mL). Understirring conditions was added DMF (0.5 mL), and the stirring wascontinued for 1 hour. The solvent and excess oxalyl chloride wereremoved in vacuo, and the residue was dissolved in CH₂Cl₂, followed bythe addition of product from step (b) (5.8 g) and pyridine (7.36 mL).The reaction solution was stirred at room temperature overnight. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in EtOAc (500 mL), washed with saturated NaHCO₃ solution (2×50mL), water (50 mL), 1N HCl solution (2×50 mL), and brine (50 mL). Afterdrying over MgSO₄, the solvent was removed in vacuo to give the crudeproduct which was purified by recrystallization from EtOAc/hexane toafford 8.4 g of the title compound.

(d)5-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzofuran-2-carboxylicacid

The product from step (c) (8.1 g) was dissolved in THF (100 mL) andmethanol (100 mL). Under stirring conditions was added LiOH (2 g) inwater (100 mL). The reaction mixture was stirred at room temperature for30 minutes. The reaction solution was then concentrated in vacuo,acidified by adding 1 N HCl solution. The product was extracted withether (2×300 mL), and combined organic layers were washed with brine(2×50 mL) and then dried over MgSO₄. The organic layer was thenconcentrated in vacuo to give the crude product which was purified byrecrystallization from ether/hexane to give 7.1 g of the title compound.

(e)5-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-benzofuran-2-carboxylicacid [2-oxo-1-phenyl-2-(propylamino)ethyl]amide.

The product from step (d) (100 mg, 0.235 mmol),(S)-N-propyl-2-phenylglycinamide hydrochloride salt (1 eq.) and PyBrop(1.1 eq.) were dissolved in CH₂Cl₂ (2 mL), followed by the addition ofdiisopropylethylamine (3 eq.), and the reaction mixture was stirred atroom temperature between 2 hours. The solvent was then evaporated, andthe product was purified by prep-TLC using 2:1 EtOAc/hexane as elutingsolvent, and the yield was 79 mg.

Examples 100-112 were prepared similarly to Example 99. In Examples 102,103 and 108, R⁶ and R⁷ together with the nitrogen atom to which they areattached form the listed heterocyclyl group.

TABLE 8

Ex- am- Mol wt MS HPLC ple R⁶ R⁷ (calc) (found) (min) 100 HCyclopropylmethyl 611.626 612.2 15.311 101 H Cyclopropyl 597.599 598.213.539 102 Piperidin-1yl 625.653 626.2 17.696 103 Morpholin-4-yl 627.626628.2 13.755 104 H Cyclopentyl 625.653 626.2 16.677 105 H3-fluoro-benzyl 665.65 666.2 16.705 106 H 2-methyl-but-1-yl 627.6689628.2 17.825 107 Methyl Methyl 585.588 586.2 14.26 108 Azetidinyl597.599 598.2 13.51 109 H 4-methoxy-benzyl 677.686 678.2 16.075 110 H3,4-difluoro-benzyl 683.6409 684.2 16.955 111 H 2,3-difluoro-benzyl683.6409 684.2 16.961 112 H 2-fluoro-4-trifloromethyl- 733.6489 733.218.899 benzyl

Table 9 below provides Examples of additional compounds of theinvention, prepared according to the methods described above, inparticular, as described for Examples 66-85.

TABLE 9

Ex- am- Mol. Wt. MS HPLC ple R¹ (calc) (found) (min) 113 Isopropylmethyl524.668 525.2 14.958 114 2-methoxy-phenyl 560.658 561.2 15.07 1152-methyl-5-chloro-phenyl 579.104 579.2 16.683 1161-hydroxy-cycloprop-1-yl 552.679 553.2 13.013 1172-methyl-4-chloro-phenyl 579.104 579.2 16.651 118 (Norborn-2-yl)-methyl562.718 563.2 17.288 119 Cyclobutyl 508.625 509.2 11.734 120phenoxy-ethyl-methyl 588.712 589.2 17.118 121 5-bromo-fur-2-yl 599.489600.2 14.651 122 1-phenyl-cyclopent-1-yl 598.751 599.2 18.913 123Naphth-1-yl 580.692 581.2 15.995 124 3-chloro-thien-2-yl 571.102 571.215.847 125 Perfluoroethyl 572.539 573.2 16.771 1262-(pyrrol-1-yl)-phenyl 595.707 596.2 15.497 127 Isoquinolin-1-yl 581.68582.2 16.432

Pharmaceutical Compositions

Oral solid forms for compounds of the invention, examples of which havebeen provided above, are preferably tablets, powders or granules whichtypically contain just the active agent(s) or preferably in combinationwith adjuvants/excipients to enhance the processing characteristics ofthe active.

For tablets, the active agent is typically less than 50% (by weight) ofthe formulation and preferably less than 10%, for example 2.5% byweight. The predominant portion of the formulation comprises fillers,diluents, disintegrants, lubricants and optionally, flavors. Thecomposition of these excipients is well known in the art. According tothis invention, the preferred fillers/diluents comprise admixtures oftwo or more of the following components: avicel, mannitol, lactose (alltypes), starch, and di-calcium phosphate. The filler/diluent admixturestypically comprises less than 98% of the formulation and preferably lessthan 95%, for example 93.5%. The preferred disintegrants includeAc-di-sol, Explotab™, starch and sodium lauryl sulphate (SLS)—also knownas wetting agent. When present these agents usually comprise less than10% of the formulation and preferably less than 5%, for example 3%. Thepreferred lubricant is magnesium stearate. When present this agentusually comprises less than 5% of the formulation and preferably lessthan 3%, for example 1%. When present these agents comprise less than60% of the formulation, preferably less than 40%, for example 10-20%.More detailed examples of tablet formulations for the compounds of theinvention are shown in Table 10.

The examples shown in Table 10 can be manufactured by standardtabletting processes, for example, direct compression or a wet, dry ormelt granulation, melt congealing process and extrusion. The tabletcores may be mono or multi-layer(s) and can be coated with appropriateovercoats known in the art.

TABLE 10 Examples of tablet formulations for compounds of formula 1,2.5% for all formulations below. Disintegrant/ Fillers/Diluents WettingAgent Flavors Lubricant Avicel/Mannitol Ac-Di-Sol — Magnesium 1:2(93.5%) 3% Stearate 1% Mannitol/Dcp Ac-Di-Sol — Magnesium 2:1 (93.5%) 3%Stearate 1% Avicel/Dcp Ac-Di-Sol — Magnesium 2:1 (93.5%) 3% Stearate 1%Avicel/ Ac-Di-Sol — Magnesium Fast Flo Lactose 3% Stearate 1:2 (93.5%)1% Avicel/Mannitol Ac-Di-Sol Brewers Yeast Magnesium 1:2 (73.5%) 3% 20%Stearate 1% Mannitol/Dcp Ac-Di-Sol Brewers Yeast Magnesium 2:1 (73.5%)3% 20% Stearate 1% Avicel/Mannitol Ac-Di-Sol Magnesium 1:2 (92.5%) 3% +Sls Stearate 1% 1% Avicel/Mannitol Ac-Di-Sol Brewers Yeast Magnesium 1:2(72.5%) 3% + Sls 20% Stearate 1% 1% Avicel/Mannitol Explotab — Magnesium1:2 (92.5%) 4% Stearate 1% Avicel/Mannitol Ac-Di-Sol — Sodium Stearyl1:2 (93.5%) 3% Fumarate 1% Avicel/Dcp Ac-Di-Sol Yeast Extract Magnesium2:1 (62.5) 3% 10% Stearate Sls = 1% Brewers Yeast 1% 20%

Oral liquid forms of the compounds of the invention are preferablysolutions, wherein the active compound is fully dissolved. Examples ofsolvents include all pharmaceutically precedented solvents suitable fororal administration and preferably those in which the compounds of theinvention show good solubility i.e., polyethylene glycol, polypropyleneglycol, edible oils and glyceryl- and glyceride-based systems. Glyceryl-and glyceride-based systems may preferably include the following agents(and similar chemicals thereof), for example: Captex 355 EP, CrodamolGTC/C, or Labrafac CC, triacetin, Capmul CMC, Migyols (812, 829, 840),Labrafil M1944CS, Peceol and Maisine 35-1. The exact composition ofthese agents and commercial sources are shown in Table 11. Thesesolvents usually make up the predominant portion of the formulationi.e., greater than 50% and preferably greater than 80%, for example 95%and more preferably greater than 99%. Adjuvants and additives may alsobe included with the solvents principally as taste-mask agents,palatability and flavoring agents, antioxidants, stabilizers, textureand viscosity modifiers, and solubilizers.

TABLE 11 Trademark, chemical composition and commercial source for someglyceryl and glyceride-based systems Commercial Trademark Chemicalcomposition Source Triacetin Glyceryl triacetate Abitec Capmul CMCGlyceryl caprylate/caprate Abitec Miglyol 812 Trigylceridecaprate/succinate Condea Miglyol 829 Trigylcerideaprylate/caprate/succinate Condea Miglyol 840 Propylene glycoldicaprylate/dicaprate Condea Labrafil Oleoyl macrogol-6-glyceridesGattefosse M1944CS Maisine 35-1 Glyceryl monolinoate Gattefosse PeceolGlyceryl monooleate Gattefosse Captex 355 EP Medium-chain triglycerideAbitec Crodamol GTC/C Medium-chain triglyceride Croda Labrafac CCMedium-chain triglyceride GattefosseA preferred oral solution for active compounds of the invention containsup to 1% by weight of active ingredient dissolved in medium-chaintriglyceride oils Pharm. Eur. or similar solvents (see table 11).

A more preferred solution contains active compound(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide,of the invention see Example 44, at a concentration up to 0.6 mg per mLin a medium-chain triglyceride oil Pharm. Eur.

A particulary preferred solution contains active compound(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide,of the invention see Example 44, at a concentration up to 0.6 mg per mLin Captex 355 EP, Crodamol GTC/C, or Labrafac CC.

An even more preferred solution contains active compound(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide,of the invention see Example 44, at a concentration of 0.5 mg of per mLin Captex 355 EP, or Crodamol GTC/C.

The preferred solutions above may be prepared in a process involvingcombining the components with mechanical or ultrasonic agitation at atemperature, in such a fashion that is advantageous to the rate ofdissolution.

A more preferable process involves combination of the components withmechanical agitation at a temperature up to 70° C., followed byfiltration to ensure solution clarity.

A particularly preferable process involves addition of the activeingredient(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide,of the invention see Example 44, with mechanical agitation, to theCaptex 355 EP, Crodamol GTC/C, or Labrafac CC that has been pre-heatedto a temperature up to 70° C., followed by cooling and filtration toensure solution clarity.

An even more preferable process involves addition of the activeingredient(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide,of the invention see Example 44, with mechanical agitation, to theCaptex 355 EP, Crodamol GTC/C, that has been pre-heated to a temperature50° C.-70° C., followed by cooling and filtration to ensure solutionclarity.

The invention is not to be limited in scope by the specific embodimentsdescribed which are intended as single illustrations of individualaspects of the invention, and functionally equivalent methods andcomponents are within the scope of the invention. Indeed, variousmodifications of the invention, in addition to those shown and describedherein will become apparent to those skilled in the art from theforegoing description and following examples. Such modifications areintended to fall within the scope of the appended claims.

All references cited herein are incorporated by reference in theirentireties for all purposes.

1. A compound of formula 1b:

or a pharmaceutically acceptable salt thereof, wherein: R¹ issubstituted at the 5 or 6 position of formula 1b and has the structure:

or when R⁷ is pyridyl or pyridyl-Z¹- optionally substituted with one tofive independently selected R¹², R¹ is (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₅-C₁₀)bicycloalkyl, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵, —SO₂R¹⁵, aryl or —(CR^(a)R^(b))_(q)-aryl, whereinthe cycloalkyl or aryl moiety is optionally substituted with from one tofive independently selected R¹⁶; m is an integer from 0 to 5; n is aninteger from 0 to 3; p is an integer from 0 to 3; L is —C(O)N(R⁹)—; X¹is N(R⁴); X² is N; R², R⁸, R¹¹, R¹², R¹³ and R¹⁶ are each independentlyselected from halo, cyano, nitro, azido, amino, hydroxy, (C₁-C₆)alkyl,(C₂-C₆)alkoxy, methoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- ortri-halo(C₂-C₆)alkyl, perfluoro(C₂-C₄)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₅)alkyl, mono-, di- or tri-halo(C₂-C₆)alkoxy,trifluoromethyl(C₁-C₅)alkoxy, (C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl,hydroxy, (C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkylamino-, (C₁-C₆)dialkylamino,amino(C₁-C₆)alkyl-, —(CR^(a)R^(b))_(q)NR^(a)R¹⁴, —C(O)NR^(a)R¹⁴,—NR¹⁴C(O)R¹⁵, —NR¹⁴OR¹⁵, —CH═NOR¹⁵, —NR¹⁴C(O)OR¹⁵, —NR¹⁴S(O)_(j)R¹⁵,—C(O)R¹⁵, —C(S)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —SO₂NR^(a)R¹⁴, —S(O)_(j)R¹⁵,or —(CR^(a)R^(b))_(q)S(O)_(j)R¹⁵; each R^(a) and R^(b) is independentlyH or (C₁-C₆)alkyl; R^(c) is H or R¹¹; each q is independently an integerfrom 0 to 6; each j is independently 0, 1 or 2; R³ is H, halo,(C₁-C₆)alkyl, or mono-, di- or tri-halo(C₁-C₆)alkyl; R⁴ is H,(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, (CR^(a)R^(b))_(r)R¹⁵, —SO₂R¹⁵ or—(CR^(a)R^(b))_(q)-phenyl, wherein the phenyl moiety is optionallysubstituted with from one to five independently selected R¹⁶; each r isindependently an integer from 2 to 5; each t is independently an integerfrom 1 to 6; R⁵ and R⁹ are each independently H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₅ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵; R⁶ is H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(q)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵; R⁷ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, —(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(q)S(C₁-C₆ alkyl), (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)C(S)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵; or R⁷ is phenyl, pyridyl, phenyl-Z¹-or pyridyl-Z¹- optionally substituted with one to five independentlyselected R¹²; Z¹ is —SO₂— or —(CR^(a)R^(b))_(v)—; v is independently aninteger from 1 to 6; wherein the alkyl or cycloalkyl moiety of theforegoing R⁶ and R⁷ groups are optionally substituted independently with1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—OC(O)R¹⁵, —NR¹⁴C(O)R¹⁵, —C(O)NR^(a)R¹⁴, —NR^(a)R¹⁴, and —NR¹⁴OR¹⁵,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkenyl; and R¹⁰ is phenyl,phenyl-Z²-, wherein the phenyl moiety is optionally substituted with oneto five independently selected R¹³; Z² is —S(O)_(j)—, —O—,—(CR^(a)R^(b))_(w)—, or—(O)_(k)(CR^(a)R^(b))_(w)(O)_(k)(CR^(a)R^(b))_(q)—; w is independentlyan integer from 1 to 6; each k is independently 0 or 1; or R¹⁰ is OR¹⁷,wherein R¹⁷ is (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- ortri-halo(C₂-C₆)alkyl, perfluoro(C₂-C₄)alkyl,trifluoromethyl(C₁-C₅)alkyl, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR⁹R^(b))_(q)—, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl;each R¹⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵,—C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵, (CR^(a)R^(b))_(t)R¹⁵ or —SO₂R¹⁵; eachR¹⁵ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, wherein the alkyl,moieties of the foregoing R¹⁵ groups are independently optionallysubstituted with 1 to 3 substituents independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyland trifluoromethoxy; and wherein any of the above “alkyl”, “alkenyl” or“alkynyl” moieties comprising a CH₃ (methyl), CH₂ (methylene), or CH(methine) group which is not substituted with halogen, SO or SO₂, orattached to a N, O or S atom, optionally bears on said methyl, methyleneor methine group a substituent selected from the group consisting ofhalo, —OR^(a), —SR^(a) and —NR^(a)R^(b).
 2. The compound of claim 1,wherein L is attached to the 2 position of R¹ and to the 5 position offormula 1b.
 3. The compound of claim 2, wherein R¹⁰ is OR¹⁷ and R⁷ isphenyl-Z¹, wherein the phenyl moiety is optionally substituted with oneto five independently selected R¹².
 4. The compound of claim 3, whereinZ¹ is —CR^(a)R^(b))_(v)—.
 5. The compound of claim 2, wherein R¹⁰ isphenyl attached at the 3 position of R¹, wherein the phenyl moiety ofR¹⁰ is optionally substituted with one to five independently selectedR¹³.
 6. The compound of claim 5, wherein R⁶ is H or (C₁-C₄)alkyl.
 7. Thecompound of claim 6, wherein the carbon designated “a” in formula 1b isin the (S) absolute configuration.
 8. The compound of claim 7, whereinR¹³ is trifluoromethyl.
 9. The compound of claim 8, wherein R³ is H,halo, or (C₁-C₆)alkyl.
 10. The compound of claim 9, wherein R⁷ is(C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl.
 11. A compound of theformula 1:

or a pharmaceutically acceptable salt thereof, wherein: R¹ issubstituted at the 5 or 6 position of formula 1 and has the structure:

m is an integer from 0 to 5; n is an integer from 0 to 3; p is aninteger from 0 to 3; L is —C(O)N(R⁹)—; X is N; R², R⁸, R¹¹, R¹², R¹³ andR¹⁶ are each independently selected from halo, cyano, nitro, azido,amino, hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkoxy, methoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,perfluoro(C₂-C₄)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino-, (C₁-C₆)dialkylamino, amino(C₁-C₆)alkyl-,—(CR^(a)R^(b))_(q)NR^(a)R¹⁴, —C(O)NR^(a)R¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴OR¹⁵,—CH═NOR¹⁵, —NR¹⁴C(O)OR¹⁵, —NR¹⁴S(O)_(j)R¹⁵, —C(O)R¹⁵, —C(S)R¹⁵,—C(O)OR¹⁵, —OC(O)R¹⁵, —SO₂NR^(a)R¹⁴, —S(O)_(j)R¹⁵, or—(CR^(a)R^(b))_(q)S(O)_(j)R¹⁵; each R^(a) and R^(b) is independently Hor (C₁-C₆)alkyl; R^(c) is H or R¹¹; each q is independently an integerfrom 0 to 6; each j is independently 0, 1 or 2; R³ is H, halo,(C₁-C₆)alkyl, or mono-, di- or tri-halo(C₁-C₆)alkyl; R⁴ is H,(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)R¹⁵, —SO₂R¹⁵ or—(CR^(a)R^(b))_(q)-phenyl, wherein the phenyl moiety is optionallysubstituted with from one to five independently selected R¹⁶; each r isindependently an integer from 2 to 5; each t is independently an integerfrom 1 to 6; R⁵, R⁶ and R⁹ are each independently H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵; R⁷ is phenyl, pyridyl, or phenyl-Z¹-or pyridyl-Z¹-, wherein the phenyl or pyridyl moiety is optionallysubstituted with one to five independently selected R¹²; Z¹ is —SO₂— or—(CR^(a)R^(b))_(v)—; v is independently an integer from 1 to 6; R¹⁰ isphenyl or phenyl-Z²- wherein the phenyl moiety is optionally substitutedwith one to five independently selected R¹³; Z² is —S(O)_(j)—, —O—,—(CR^(a)R^(b))_(w)—, or—(O)_(k)(CR^(a)R^(b))_(w)(O)_(k)(CR^(a)R^(b))_(q)—; w is independentlyan integer from 1 to 6; each k is independently 0 or 1; each R¹⁴ isindependently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵,—(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl),—(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(t)R¹⁵ or —SO₂R¹⁵; each R¹⁵ isindependently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, trifluoromethyl,trifluoromethyl(C₁-C₅)alkyl, wherein the alkyl, moieties of theforegoing R¹⁵ groups are independently optionally substituted with 1 to3 substituents independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy,amino, hydroxy, halo, cyano, nitro, trifluoromethyl andtrifluoromethoxy; and wherein any of the above “alkyl”, “alkenyl” or“alkynyl” moieties comprising a CH₃ (methyl), CH₂ (methylene), or CH(methine) group which is not substituted with halogen, SO or SO₂, orattached to a N, O or S atom, optionally bears on said methyl, methyleneor methine group a substituent selected from the group consisting ofhalo, —OR^(a), —SR^(a) and —NR^(a)R^(b).
 12. The compound of claim 11,wherein L is attached to the 2 position of R¹ and to the 5 position offormula
 1. 13. The compound of claim 12, wherein m is 0, n is 0, and pis 0 or
 1. 14. The compound of claim 13, wherein R¹⁰ is phenyl-Z²-attached at the 3 position of R¹, wherein the phenyl moiety of R¹⁰ isoptionally substituted with one to five independently selected R¹³. 15.The compound of claim 13, wherein R¹⁰ is phenyl attached at the 3position of R¹, wherein the phenyl moiety of R¹⁰ is optionallysubstituted with one to five independently selected R¹³.
 16. Thecompound of claim 15, wherein R⁷ is phenyl-Z¹, wherein the phenyl moietyis optionally substituted with one to five independently selected R¹².17. The compound of claim 16, wherein Z¹ is —(CR^(a)R^(b))_(v)—.
 18. Thecompound of claim 17, wherein R⁴, R⁵, R⁶ and R⁹ are each independentlyselected from H, (C₁-C₆)alkyl, —(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl) or—(CR^(a)R^(b))_(r)R¹⁵.
 19. The compound of claim 18, wherein each R¹² isindependently selected from halo, hydroxy, (C₁-C₆)alkyl, methoxy,(C₂-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- ortri-halo(C₂-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio and hydroxy(C₁-C₆)alkyl.
 20. The compound of claim 18,wherein each R¹³ is independently selected from halo, hydroxy, amino,cyano, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, methoxy, (C₂-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, mono-, di- ortri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy, (C₁-C₆)alkylthio,hydroxy(C₁-C₆)alkyl, —C(O)OR¹⁵ and —NR¹⁴C(O)R¹⁵; wherein R¹⁴ is H or(C₁-C₆)alkyl; and wherein R¹⁵ is H or (C₁-C₆)alkyl.
 21. The compound ofclaim 20, wherein R¹⁰ is phenyl attached at the 3 position of R¹,wherein the phenyl moiety of R¹⁰ is optionally substituted with one R¹³.22. The compound of claim 21, wherein Z¹ is —CH₂—.
 23. The compound ofclaim 22, wherein R⁴ is H, (C₁-C₆)alkyl or —(CR^(a)R^(b))_(t)O(C₁-C₆alkyl).
 24. The compound of claim 23, wherein the carbon designated “a”in formula 1 is in the “(S)” configuration.
 25. The compound of claim24, wherein R¹³ is trifluoromethyl.
 26. The compound of claim 25,wherein R³ is H, halo, or (C₁-C₆)alkyl.
 27. The compound of claim 26,wherein R⁶ is methyl.
 28. The compound of claim 26, wherein R³ ischloro.
 29. The compound of claim 14, wherein Z² is O or S.
 30. Thecompound of claim 16, wherein Z¹ is O or S.
 31. The compound of claim11, wherein R⁷ is pyridyl-Z¹, wherein the pyridyl moiety is optionallysubstituted with from one to five independently selected R¹².
 32. Thecompound of claim 31, wherein Z¹ is —(CH₂)—.
 33. The compound of claim11, wherein R¹⁰ is phenyl optionally substituted with one to fiveindependently selected R¹³.
 34. The compound of claim 33, wherein R⁷ isphenyl-Z¹, wherein the phenyl moiety is optionally substituted with fromone to five independently selected R¹².
 35. A compound of the formula 2:

or a pharmaceutically acceptable salt thereof, wherein: R¹ issubstituted at the 5 or 6 position of formula 2 and has the structure:

m is an integer from 0 to 5; n is an integer from 0 to 3; p is aninteger from 0 to 3; L is —C(O)N(R⁹)—; X is N; R², R⁸, R¹¹, R¹² and R¹³are each independently selected from halo, cyano, nitro, azido, amino,hydroxy, (C₁-C₆)alkyl, (C₂-C₆)alkoxy, methoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, mono-, di- or tri-halo(C₂-C₆)alkyl,perfluoro(C₂-C₄)alkyl, trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl,mono-, di- or tri-halo(C₂-C₆)alkoxy, trifluoromethyl(C₁-C₅)alkoxy,(C₁-C₆)alkylthio, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkylamino-, (C₁-C₆)dialkylamino, amino(C₁-C₆)alkyl-,—(CR^(a)R^(b))_(q)NR^(a)R¹⁴, —C(O)NR^(a)R¹⁴, —NR¹⁴C(O)R¹⁵, —NR¹⁴OR¹⁵,—CH═NOR¹⁵, —NR¹⁴C(O)OR¹⁵, —NR¹⁴S(O)_(j)R¹⁵, —C(O)R¹⁵, —C(S)R¹⁵,—C(O)OR¹⁵, —OC(O)R¹⁵, —SO₂NR^(a)R¹⁴, —S(O)_(j)R¹⁵, or—(CR^(a)R^(b))_(q)S(O)_(j)R¹⁵; each R⁹ and R^(b) is independently H or(C₁-C₆)alkyl; R^(c) is H or R¹¹; each q is independently an integer from0 to 6; each j is independently 0, 1 or 2; R³ is H, halo, (C₁-C₆)alkyl,or mono-, di- or tri-halo(C₁-C₆)alkyl; each r is independently aninteger from 2 to 5; each t is independently an integer from 1 to 6; R⁵and R⁹ are each independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,—C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(t)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵; R⁶ is H, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, —C(O)R¹⁵, —C(S)R¹⁵, —(CR^(a)R^(b))_(q)O(C₁-C₆ alkyl),—(CR^(a)R^(b))_(q)S(C₁-C₆ alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵; y is an integer from 0 to 5; R⁷ is(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(CR^(a)R^(b))_(q)O(C₁-C₆alkyl), —(CR^(a)R^(b))_(q)S(C₁-C₆ alkyl); (C₃-C₈)cycloalkyl, —C(O)R¹⁵,—C(S)R¹⁵, —(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(r)C(S)R¹⁵,—(CR^(a)R^(b))_(r)R¹⁵ or —SO₂R¹⁵; or R⁷ is phenyl, pyridyl, phenyl-Z¹-or pyridyl-Z¹- optionally substituted with one to five independentlyselected R¹²; v is independently an integer from 1 to 6; wherein thealkyl or cycloalkyl, moiety of the foregoing R⁶ and R⁷ groups areoptionally substituted independently with 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl,trifluoromethoxy, azido, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵,—NR¹⁴C(O)R¹⁵, —C(O)NR^(a)R¹⁴, —NR^(a)R¹⁴, and —NR¹⁴OR¹⁵, C₁-C₆ alkyl,C₂-C₆ alkenyl, and C₂-C₆ alkynyl; and R¹⁰ is phenyl or phenyl-Z²-,wherein the phenyl moiety is optionally substituted with one to fiveindependently selected R¹³; Z² is —S(O)_(j)—, —O—, —(CR^(a)R^(b))_(w)—,or —(O)_(k)(CR^(a)R^(b))_(w)(O)_(k)(CR^(a)R^(b))_(q)—; w isindependently an integer from 1 to 6; each k is independently 0 or 1; orR¹⁰ is OR¹⁷, wherein R¹⁷ is (C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)alkyl,mono-, di- or tri-halo(C₂-C₆)alkyl, perfluoro(C₂-C₄)alkyl,trifluoromethyl(C₁-C₅)alkyl, hydroxy(C₁-C₆)alkyl,(C₃-C₈)cycloalkyl(CR^(a)R^(b))_(q)—, (C₂-C₆)alkenyl, or (C₂-C₆)alkynyl;each R¹⁴ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, —C(O)R¹⁵,—C(S)R¹⁵, —(CR^(a)R^(b))_(t)O(C₁-C₆ alkyl), —(CR^(a)R^(b))_(t)S(C₁-C₆alkyl), —(CR^(a)R^(b))_(r)C(O)R¹⁵, —(CR^(a)R^(b))_(t)R¹⁵ or —SO₂R¹⁵;each R¹⁵ is independently H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,trifluoromethyl, trifluoromethyl(C₁-C₅)alkyl, wherein the alkyl,moieties of the foregoing R¹⁵ groups are independently optionallysubstituted with 1 to 3 substituents independently selected from C₁-C₆alkyl, C₁-C₆ alkoxy, amino, hydroxy, halo, cyano, nitro, trifluoromethyland trifluoromethoxy; and wherein any of the above “alkyl”, “alkenyl” or“alkynyl” moieties comprising a CH₃ (methyl), CH₂ (methylene), or CH(methine) group which is not substituted with halogen, SO or SO₂, orattached to a N, O or S atom, optionally bears on said methyl, methyleneor methine group a substituent selected from the group consisting ofhalo, —OR^(a), —SR^(a) and —NR^(a)R^(b).
 36. The compound of claim 35,wherein L is attached to the 2 position of R¹ and to the 5 position offormula
 2. 37. The compound of claim 36, wherein y is 1 or
 2. 38. Thecompound of claim 37, wherein R¹⁰ is phenyl attached at the 3 positionof R¹, wherein the phenyl moiety of R¹⁰ is optionally substituted withone to five independently selected R¹³.
 39. The compound of claim 38,wherein R⁷ is phenyl-Z¹, wherein the phenyl moiety is optionallysubstituted with one to five independently selected R¹².
 40. Thecompound of claim 39, wherein Z¹ is —(CR^(a)R^(b))_(t)—.
 41. Thecompound of claim 40, wherein R⁶ is H or (C₁-C₄)alkyl.
 42. The compoundof claim 41, wherein the carbon designated “a” in formula 2 is in the(S) absolute configuration.
 43. The compound of claim 42, wherein R¹³ istrifluoromethyl.
 44. The compound of claim 43, wherein R³ is H, halo, or(C₁-C₆)alkyl.
 45. A pharmaceutical composition which comprises atherapeutically effective amount of a compound of any of claim 1, 11 or35, or a stereoisomer, pharmaceutically acceptable salt or hydratethereof in combination with a pharmaceutically-acceptable carrier ordiluent.
 46. A method of treating obesity in an animal in need oftreatment thereof, which comprises administering to the animal atherapeutically effective amount of the compound of any one of claim 1,11 or
 35. 47. A method of treating atherosclerosis; pancreatitissecondary to hypertriglyceridemia; hyperglycemia (1) by causing areduced absorption of dietary fat through MTP inhibition, (2) bylowering triglycerides through MTP inhibition or (3) by decreasing theabsorption of free fatty acids through MTP inhibition; in an animal inneed of treatment thereof, which comprises administering to the animal atherapeutically effective amount of the compound of any one of claim 1,11 or
 35. 48. A method of treating diabetes in an animal in need oftreatment thereof, which comprises administering to the animal atherapeutically effective amount of the compound of any one of claim 1,11 or
 35. 49. A method of treating obesity in an animal in need oftreatment thereof, which comprises administering to the animal atherapeutically effective amount of the compound of claim 1 or 11 andone or more anti-obesity agents.
 50. The compound of the formula:


51. The compound of the formula:

where R⁶ and R⁷ are each —C₂H₅.
 52. The compound of the formula:

where R⁶ is H and R⁷ is cyclopropylmethyl.
 53. The compound of theformula:

where R⁶ is H and R⁷ is —CH₂C₆H₅.
 54. The compound of the formula

where R⁶ is —CH₃ and R⁷ is pyridine-3-yl.